2-substituted carbonylimidazo[4,5-c]quinolines

ABSTRACT

2-Substituted carbonylimidazo[4,5-c]quinolines of formula: ##STR1## having a high affinity for benzodiazepin receptor and showing an excellent psychostimulating action orally at a dose of 0.1-500 mg are provided through several routes.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to imidazo[4,5-c]quinolines substituted by a carbonyl group at the 2-position.

2. Prior Art

As to compounds having an imidazo[4,5-c]quinoline ring as a basic structure, Abbasi, et al. in Monatsh. Chem., 111, 963 (1980) have shown 3-hydroxy-2-hydroxymethyl-8-methoxy-9-nitro-4-styryl-2H-imidazo[4,5-c]quinoline derivatives as intermediates for synthesizing physiologically active substances. European Pat. No. 145,340 discloses 2-hydroxyalkyl-1H-imidazo[4,5-c]quinolines as bronchodilators or antiviral drugs.

SUMMARY

This invention relates to compounds of the formula: ##STR2## wherein R is (1) hydrogen; (2) hydroxy; (3) C₁ -C₁₀ alkyl optionally substituted by halogen, C₁ -C₅ alkylthio, C₁ -C₅ alkoxycarbonyl, or phenyl; (4) C₃ -C₅ cycloalkyl optionally substituted by C₁ -C₅ alkyl; (5) C₂ -C₅ alkenyl optionally substituted by C₁ -C₅ alkyl or di-C₁ -C₅ alkyl; (6) C₁ -C₅ alkoxy; (7) phenoxy; (8) amino optionally substituted by C₁ -C₅ alkyl or di-C₁ -C₅ alkyl; (9) phenyl optionally substituted by one or two members independently selected from the group consisting of halogen, trifluoromethyl, C₁ -C₅ alkoxy, and C₁ -C₅ alkylthio; or (10) 5- or 6-membered heterocyclic group optionally substituted by one or two members independently selected from the group consisting of halogen, C₁ -C₅ alkyl, and phenyl; Q is hydrogen, C₁ -C₅ alkyl, benzyl, benzhydryl, trityl, C₁ -C₁₃ acyl, C₁ -C₅ alkylsulfonyl, or C₆ -C₁₂ arylsulfonyl, provided that Q is located at nitrogen atom of 1-, 3-, or 5-position; R¹ and R² each is hydrogen, C₁ -C₅ alkyl, C₁ -C₅ alkoxy, or halogen; and the dotted lines indicate the presence of three double bonds at the position of 2(3), 3a(9b), 4(5); 1(9b), 2(3), 3a(4); or 1(2), 3a(9b), 4(5); or a pharmaceutically acceptable acid addition salt, and also relates to psychotropic agents containing the compound as an active ingredient.

DESCRIPTION OF THE PREFERRED EMBODIMENT

Compounds having the aforementioned basic structure have been widely studied. However, none of them were found to have any psychotropic activity. The present inventors have found that the above-mentioned imidazo[4,5-c]quinoline derivatives have utility as psychotropic agents (e.g. U.S. Pat. No. 4753951). In addition, they found that the compounds of the present invention having a carbonyl group at the 2-position have excellent psychotropic activity, based upon the activation of benzodiazepine receptors. Especially, these are expected as psychostimulants, based upon the potentiation of pentylenetetrazole (PTZ)-induced convulsions. So the compounds (I) of present invention may be useful for treatment of depression, convulsion, anxiety, amnesia, senile dementia, or cerebral disorders etc.

The terms used in the above definitions are explained below.

As the alkyl, there are exemplified straight or branched alkyl, such as methyl, ethyl, propyl, butyl, isobutyl, t-butyl, sec-butyl, pentyl, neopentyl, etc.

As the alkoxy, there are, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, etc.; and as the alkylthio, there are, for example, methylthio, ethylthio, propylthio, butylthio, isobutylthio, neopentylthio, etc.

As the cycloalkyl, there are exemplified cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

As the alkenyl, there are, for example, vinyl, 1-propenyl, 2-propenyl, 1-isobutenyl, butenyl, isopentenyl, pentenyl, etc.

As the halogen, there are fluorine, chlorine, bromine and iodine.

As the 5- or 6-membered heterocyclic group, there are exemplified isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, thiadiazolyl, oxadiazolyl, thienyl, furyl, pyridyl, etc.

The compound (I) of the present invention can be obtained through the following four routes: ##STR3## (wherein R, R¹ and R² have the same meaning as defined above; Q¹ is hydrogen or alkyl; and Q² is alkyl, benzyl, benzhydryl, or trityl.)

1ST STEP

The objective 2-carbonyl compound (Ia) is obtained by reacting the starting material (II) with an acylating agent or carbamoylating agent in the presence of a lithium-type base such as n-BuLi, sec-BuLi, t-BuLi, or PhLi. This reaction is carried out at a low temperature (about -50˜about -80° C.) usually in an appropriate solvent, using an acylating agent or carbamoylating agent corresponding to the required acyl or amide group, respectively.

As the solvent, ether-type solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, etc. are exemplified.

As the acylating agent, acid halide, carboxylate, acid anhydride, mixed acid anhydride, etc. may be used.

As the carbamoylating agent, there may be used dimethylcarbamoyl halide and isocyanates such as alkyl isocyanate and phenyl isocyanate.

2ND STEP

The imidazo[4,5-c]quinoline (III) having a substituent at the 1-, 3-, or 5-position is obtained by reacting the starting material (II) with an appropriate alkylating agent for several hours in a suitable solvent in the presence of a base.

As the alkylating agent, there are, for example, alkyl halides such as methyl iodide and ethyl iodide; benzyl halides such as benzyl chloride; and benzhydryl bromide, trityl chloride, etc.

Comparatively bulky groups such as trityl are mainly introduced to the 3-position, while in case of less bulky alkyls such as methyl, ethyl, or propyl, compounds having substituents at the 1- or 5-position in addition to the 3-position are obtained as a mixture.

As the solvent, acetonitrile, tetrahydrofuran, ether, dioxane, dimethylformamide, etc. are exemplified.

As the base, triethylamine, pyridine, sodium ethylate, sodium hydride, etc are exemplified.

The reaction is completed in 5˜30 hours if performed at about 0°˜about 50° C., preferably at room temperature.

3RD STEP

The objective compound (Ib) is obtained by acylating or carbamoylating the compound (III) in the same manner as in the 1st Step.

4TH STEP

The above-mentioned 2-carbonyl compound (Ib) is dealkylated by treating with a suitable reagent at about 0°˜about 50° C., preferably at room temperature, whereby the objective compound (Ic) is obtained. As the reagent for dealkylation, trifluoroacetic acid, hydrogen iodide, boron tribromide, etc. are preferable. ##STR4## (Wherein R¹, R², and Q¹ have the same meanings as defined above.)

1ST STEP

4-Amino-3-formylaminoquinoline (IV) is obtained by reacting 3,4-diaminoquinoline (V) with formic acid under heating for several hours. The reaction may be carried out at about 80°˜about 110° C. for 1-3 hours.

However, when Q¹ is not H, the compound (II) is directly obtained by this reaction in some cases.

2ND STEP

1H-Imidazo[4,5-c]quinoline compound (II) may be obtained by heating under reflux the above obtained compound (IV) obtained above in a solvent for several hours.

As the solvent, the solvents having high boiling point, for instance, alcohols such as ethylene glycol and ethers such as diglyme, and the like are exemplified.

The reaction may be carried out at about 100°˜about 200° C. for 1-5 hours. ##STR5## (wherein R¹, R², and Q¹ have the same meanings as defined above; Y is alkyl, cycloalkyl or aryl.)

1ST STEP

4-Amino-3-substituted acetamidoquinoline (VI) is obtained by reacting a substituted acetyl halide with the compound (V) in an appropriate solvent.

As the solvent, there are exemplified hexamethylphosphoramide, acetonitrile, dimethylformamide, chloroform or a mixture thereof.

The reaction is completed in 0.5˜5.0 hours if performed at about -50°˜about 5° C., preferably at about -10°˜about 0° C.

2ND STEP

2-Substituted methyl-1H-imidazo[4,5-c]quinoline compound (VII) is obtained by heating the amide (VI) above for several minutes under reflux in a solvent.

As the solvent, solvents having high boiling point are preferable. They are, for instance, alcohols such as ethylene glycol, etc. and ethers such as diglyme, etc. The reaction is carried out for 10˜40 minutes at about 100°˜about 200° C.

3RD STEP

The objective compound (Id) is obtained by heating the compound (VII) as obtained above with an oxidizing agent for several hours in an appropriate solvent.

As the solvent, dioxane, 1,2-dimethoxyethane, acetone, benzene, etc. are exemplified.

As the oxidizing agent, there are exemplified selenium dioxide, manganese dioxide, chromic anhydride, potassium permanganate, etc.

The reaction is completed in 1-3 hours if carried out at about 60°˜about 90° C. ##STR6## (wherein R¹, R², and Q¹ have the same meanings as defined above; R³ is alkyl or aryl.)

1ST STEP

4-Amino-3-(trichloroacetimidoylamino)quinoline (VIII) is obtained by reacting methyltrichloroacetimidate with the compound (V) in an appropriate solvent, and then by stirring for several hours at room temperature.

As the solvent, acetic acid is preferable.

The reaction is carried out for 1-5 hours at about 0°˜about 50° C., preferably at room temperature.

2ND STEP

The objective compound (Ie) is obtained by reacting the compound (VIII) obtained above with a suitable alcohol or phenol under reflux or heating for several hours. As the alcohols there may be used, for example, methanol, ethanol, n-propyl alcohol, isopropyl alcohol, etc.

The phenols include cresols and naphthols as well as phenols.

The reaction is completed in 1-5 hours if carried out at about 60°˜about 200° C. ##STR7## (wherein R¹, R², and Q¹ have the same meanings as defined above; R⁴ and R⁵ each is hydrogen or alkyl.)

1ST STEP

The carboxylic acid (If) is obtained by reacting the ester (Ic) or (Ie) with a base in an appropriate solvent for several hours.

As the solvent, there are exemplified methanol, ethanol, isopropanol, water or a mixture thereof. As the base, sodium hydroxide, potassium hydroxide, and the like are preferable.

This hydrolysis is carried out at about 10°˜about 100° C. for 1-5 hours.

2ND STEP

The carboxylic acid (If) thus obtained is at first converted into an acid halogenide by the reaction with a halogenating agent such as thionyl chloride, etc. and the resulting halogenide is allowed to react with an appropriate amine (IX) to give the amide (Ig).

As the amines, there are exemplified N,N-dimethylamine, N,N-diethylamine, monomethylamine, monobutylamine, etc.

The reaction is carried out at about 0°˜about 50° C., preferably at room temperature for 10˜40 minutes. The reaction of the 2nd step may follow the 1st Step successively without isolation of the compound (If).

3RD STEP To a solution of the compound (Ic) or (Ie) in an appropriate solvent is added a suitable amine, and the mixture is heated at about 60°˜about 150° C. for 1-5 hours in a sealed tube, whereby the objective compound (Ig) is obtained.

As the solvent, alcohols such as methanol and ethanol, etc. or water are exemplified. ##STR8## (wherein Q³, Q⁴, and Q⁵ each is alkyl, acyl, alkylsulfonyl or arylsulfonyl; and R¹, R², R³, R⁴, R⁵, and Y have the same meanings as defined above.)

The objective compound (Id), (Ie) and (Ig) obtained in the Routes B, C and D may be subjected to the reaction for indroducing substituent Q if Q' is hydrogen.

This reaction may be carried out by treating the compound (Id), (Ie) or (Ig) with a suitable reagent in the presence of a base for several hours in an appropriate solvent.

As the reagent, alkyl halide such as methyl iodide and ethyl iodide, etc.; acid halide, acid anhydride, sulfonyl chloride, etc. are exemplified.

As the solvent, there are, for example, acetonitrile, tetrahydrofuran, ether, dioxane, dimethylformamide, etc.

As the base, triethylamine, sodium alcoholate, sodium hydride, etc. are exemplified.

The reaction is completed in 5˜30 hours if performed at about 0°˜about 50° C., preferably at room temperature.

The objective compound (I) can be converted into its pharmaceutically acceptable acid addition salts such as salts with inorganic acids including hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, etc.; and organic acids including acetic acid, maleic acid, malic acid, citric acid, lactic acid, methanesulfonic acid, etc. The compounds (I) or the pharmaceutically acceptable acid addition salts show high affinities for benzodiazepine receptors and are useful as psychotropic agents such as psychostimulants or antianxiety agents.

The compounds (I) can be administered orally or parenterally to humans or mammals. They may be formulated in a conventional manner into tablets, capsules, pills, granules, injections, suppositories and syrups. The pharmaceutically acceptable carriers, diluents, and excipients illustratively include lactose, sucrose, wheat starch, potato starch, magnesium stearate, gelatin, methyl cellulose, agar, water and the like. If necessary, stabilizers, emulsifiers, wet extenders, buffers and other pharmaceutical auxiliaries may appropriately be added. An optimum daily dosage is 0.1˜500 mg orally, and 0.1˜300 mg injectably, in one to three divided doses.

The present invention is explained in more detail by the following Examples, Referential Examples, which are not intended to limit the scope of the invention.

The reactions shown in the Examples and Referential Examples are usually carried out in an anhydrous solvent under a nitrogen atomosphere. For the drying of extracting solvents, anhydrous magnesium or sodium sulfate is used. For chromatography on a column of silica gel, Kiesel gel 60 (70-230 mesh) made by Merck is used.

Abbreviations used in the Examples, Referential Examples and Tables have the following meanings:

Tr: trityl; Me: methyl; Et: ethyl; THF: tetrahydrofuran; MeOH: methanol, EtOH: ethanol; AcOEt: ethyl acetate; DMF: dimethylformamide; HMPA: hexamethylphosphoramide; MeCN: acetonitrile; (d): decomposition; (s): sublimation.

In the NMR spectrum, the indication of multiplicity is abbreviated as follows:

s: singlet; d: doublet; t: triplet; q: quartet; m:multiplet.

EXAMPLE 1 2-Cyclopropylcarbonyl-1H-imidazo[4,5-c]quinoline (Ic-1) ##STR9##

To a cold solution (-70° C.) of 1.23 g of 3-trityl-3H-imidazo[4,5-c]quinoline (III-1) in 25 ml of THF was added dropwise a mixture of 3 ml of 1.6M solution of n-butyl lithium in hexane and 3 ml of THF while being kept at -72°˜-68° C. The mixture was stirred at the same temperature for 30 min., whereby a yellow solution of 2-lithio form (III-1') was obtained. All the 2-lithio form used in the Examples hereafter are prepared according to the same reaction conditions. To the yellow solution of the compound (III-1') was added 1.04 g of cyclopropanecarbonyl chloride all at once. The temperature of the reaction solution was gradually elevated to room temperature, and the solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous ammonia. The organic layer was washed with water and saturated brine, successively, and dried. The ethyl acetate was removed by evaporation, and the residue was crystallized from n-hexane--ethyl acetate to give 900 mg of the crude crystals (Ib-1). The compound (Ib-1) was deprotected by mixing with 4 ml of trifluoroacetic acid. After stirring for 30 min. at room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with water and saturated brine, and dried. The ethyl acetate was removed by evaporation, and the residue was chromatographed on a column of silica gel for purification. The fraction eluted with chloroform--methanol (30:1 v/v) was concentrated and crystallized from -hexane to give 395 mg (yield: 56%) of the titled compound (Ic-1). This was recrystallized from ethanol to give colorless crystals melting at 230° C. (dec.).

Anal. Calcd. (%) for C₁₄ H₁₁ N₃ O : C, 70.87; H, 4.67; N, 17.71. Found (%): C, 70.85; H, 4.84; N, 17.53.

NMR (DMSO-d₆) δ: 1.23 (4H, d), 3.35 (1H, quintet), 7.60˜7.85 (2H, m), 8.05˜8.25 (1H, m), 8.55˜8.75 (1H, m), 9.33 (1H, s).

EXAMPLE 2 2-Isobutyryl-7-methoxy-1H-imidazo[4,5-c]quinoline (I c-2) ##STR10##

A solution of 1.32 g of 7-methoxy-3-trityl-3H-imidazo[4,5-c]quinoline (III-2) in 30 ml of THF was reacted with a mixture of 2.5 ml of 1.6M solution of n-butyl lithium in hexane and 2 ml of THF under the same conditions as in Example 1. To this was added 1.33 g of isobutyric anhydride. The reaction mixture was gradually warmed up to room temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous ammonia; and the organic layer was washed with water, then with saturated brine and dried. The ethyl acetate was removed by evaporation, and the residue was chromatographed on a column of silica gel for purification. The fraction eluted with ethyl acetate-n-hexane (1:2 v/v) was concentrated and crystallized from n-hexane to give 1.20 g of the objective compound (I b-2). The compound (I b-2) was dealkylated by mixing with 4 ml of trifluoroacetic acid. After treatment as in Example 1, the residue was chromatographed on a column of silica gel for purification. The fraction eluted with chloroform-methanol (30:1 v/v) was concentrated to give 580 mg (yield: 72%) of the titled compound (I c-2) as crystals. This was crystallized from ethanol to give colorless crystals melting at 283°˜285° C.

Anal. Calcd. (%) for C₁₅ H₁₅ N₃ O₂ : C, 66,90; H, 5.61; N, 15.60. Found (%): C, 67.07; H, 5.56; N, 15.74.

NMR (DMSO-d₆) δ: 1.25 (6H, d), 3.93 (1H, septet), 3.97 (3H, s), 7.40 (1H, d, d), 7.57 (1H, d), 8.53 (1H, d), 9.28 (1H, s).

EXAMPLES 3˜32

In the same manner as in Examples 1 or 2, the objective compounds (I c) were obtained under reaction conditions shown in Table 1. The physical properties of the objective compounds were shown in Tables 2-1 and 2-2.

    TABLE 1       ##STR11##        1st Step 2nd Step Compound (Ic) Amount of Compd. (III) n-BuLi-THF RCOX C      F.sub.3 CO.sub.2 H Yield  Ex No. R R.sup.1 R.sup.2 (g) Solvent THF (ml)      (ml) (ml) X (g) (ml) (mg) (%) Compd. No.        3 CH.sub.3 H H 1.23 30 4 4 OCOCH.sub.3 1.3 6 290 46 Ic-3  4 C.sub.2      H.sub.5 H H 1.23 25 2.5 2 Cl 0.75 4 295 44 Ic-4  5 C.sub.2 H.sub.5 7-OMe      H 1.32 30 2.5 2 Cl 0.75 4 365 48 Ic-5  6 (CH.sub.2).sub.2 CH.sub.3 H H      1.23 25 2.5 2  OCO(CH.sub.2).sub.2 CH.sub.3 1.26 4 265 37 Ic-6  7      (CH.sub.2).sub.3 CH.sub.3 H H 1.23 25 2.5 2 OCO(CH.sub.2).sub.3 CH.sub.3      1.50 4 450 61 Ic-7  8 (CH.sub.2).sub.4 CH.sub.3 H H 1.23 25 2.5 2      OCO(CH.sub.2).sub.4 CH.sub.3 1.85 4 355 44 Ic-8  9 (CH.sub.2).sub.5      CH.sub.3 H H 1.23 25 2.5 2 OCO(CH.sub.2).sub.5 CH.sub.3 2.10 4 580 69      Ic-9  10 (CH.sub.2).sub.6 CH.sub.3 H H 1.23 25 2.5 2 Cl 1.33 4 240 27      Ic-10 11 (CH.sub.2).sub.7 CH.sub.3 H H 1.23 25 2.5 2 Cl 1.47 3 260 29      Ic-11 12 (CH.sub.2).sub.8 CH.sub.3 H H 1.23 25 2.5 2 Cl 1.56 4 270 28      Ic-12 13 (CH.sub.2).sub.9 CH.sub.3 H H 1.23 25 2.5 2 Cl 1.65 4 290 29      Ic-13 14 CH(CH.sub.3).sub.2 H H 1.23 25 2.5 2 OCOCH(CH.sub.3).sub.2 0.95      4 150 21 Ic-14 15 CH(CH.sub.3).sub. 2 7-F H 1.42 70 2.8 2 Cl 0.94 3 124      15 Ic-15 16 CH(CH.sub.3).sub.2 8-F H 1.29 70 2.5 2 Cl 0.85 4 240 31      Ic-16 17 CH(CH.sub.3).sub.2 8-Me H 1.27 27 2.5 2 OCOCH(CH.sub.3).sub.2      1.33 4 550 73 Ic-17       18      ##STR12##       H H 1.23 25 2.5 2 Cl 0.99 4 350 46 Ic-18  19 CH.sub.2       CH(CH.sub.3).sub.2 H H 1.23 25 2.5 2 OCOCH.sub.2 CH(CH.sub.3).sub.2      1.50 4 470 62 Ic-19       20      ##STR13##       7-F H 1.72 80 3.2 2 Cl 1.07 3 430 42 Ic-20       21      ##STR14##       8-F H 1.72 80 3.2 2.5 Cl 1.07 4 580 57 Ic-21       22      ##STR15##       7-OMe H 1.32 30 2.5 2 Cl 1.04 4 460 58 Ic-22       23      ##STR16##       8-Me H 1.27 27 2.5 2 Cl 1.04 4 425 57 Ic-23       24      ##STR17##       H H 1.23 25 2.5 2 Cl 0.95 3 350 47 Ic-24       25      ##STR18##       H H 1.23 25 2.5 2 Cl 1.50 3 300 40 Ic-25       26      ##STR19##       H H 1.23 25 2.5 2 Cl 1.00 4 290 37 Ic-26       27      ##STR20##       H H 1.23 25 2.5 2 Cl 0.93 4 100 14 Ic-27       28      ##STR21##       H H 1.23 25 2.5 2 Cl 0.90 2 110 15 Ic-28       29      ##STR22##       H H 1.23 25 2.5 2 Cl 0.96 3 350 47 Ic-29  30 (CH.sub.2).sub.3 Cl H H      1.23 25 2.5 2 Cl 1.13 2 120 15 Ic-30 31 (CH.sub.2).sub.2 SCH.sub.3 H H      1.23 25 2.5 2 Cl 2.00 2 160 20 Ic-31       32      ##STR23##       H H 1.23 25 2.5 2 Cl 1.20 2 195 22 Ic-32

    TABLE 2       ##STR24##            Recrystal-  Elementary Analysis (%)  Compd.  m.p. Appear- lizing      Molecular Up (Calcd.), Down (Found) No. R.sup.1 R.sup.2 R (°C.)      ance Solvent Formula C H N  NMR (DMSO-d.sub.6) δ        Ic-3  H H CH.sub.3  247-250(d) Colorless EtOH C.sub.12 H.sub.9 N.sub.3      O 68.24 4.29 19.89  2.80 (3H, s), 7.60˜7.90 (2H, m), 8.05˜8.3      0 (1H, m), 8.55˜         67.99 4.35 19.56  8.75 (1H, m), 9.33 (1H,      s) Ic-4  H H C.sub.2 H.sub.5 230(d) Colorless EtOH C.sub.13 H.sub.11      N.sub.3 O 69.32 4.92 18.65  1.20 (3H, t), 3.27 (2H, q), 8.60˜8.90      (2H, m), 8.05˜8.25         69.41 4.99 18.56  (1H, m), 8.55˜8.      75 (1H, m), 9.32 (1H, s) Ic-5  7-OMe H C.sub.2 H.sub.5 295(d) Light      yellow EtOHCHCl.sub.3 C.sub.14 H.sub.13 N.sub.3 O.sub.2 65.87 5.13 16.46       1.18 (3H, t), 3.27 (2H, q), 3.93 (3H, s), 7.37 (1H, d, d),      65.71 5.23 16.45  7.57 (1H, d), 8.53 (1H, d), 9.27 (1H, s) Ic-6  H H      (CH.sub.2).sub.2 CH.sub.3 236-238 Colorless EtOH C.sub.14 H.sub.13      N.sub.3 O 70.26 5.48 17.56  0.98 (3H, t), 1.55˜1.98 (2H, t), 3.25      (2H, t), 7.65˜7.90         70.27 5.57 17.51  (2H, m), 8.05˜8.      30 (1H, m), 8.55˜8.80 (1H, m), 9.33             (1H, s) Ic-7  H H      (CH.sub.2).sub.3 CH.sub.3 229-231 Colorless EtOH C.sub.15 H.sub.15      N.sub.3 O 71.13 5.97 16.59  0.93 (3H, t), 1.15˜1.90 (4H, m), 3.27      (2H, t), 7.65˜7.90         71.36 6.05 16.60  (2H, m), 8.10˜8.      35 (1H, m), 8.55˜8.80 (1H, m), 9.33             (1H, s) Ic-8  H H      (CH.sub.2).sub.4 CH.sub.3 214-216 Colorless AcOEt C.sub.16 H.sub.17      N.sub.3 O 71.89 6.41 15.72  0.90 (3H, t), 1.10˜1.90 (6H, m), 3.25      (2H, t), 7.60˜7.90         72.14 6.48 15.70  (2H, m), 8.05˜8.      30 (1H, m), 8.55˜8.80 (1H, m), 9.33             (1H, s) Ic-9  H H      (CH.sub.2).sub.5 CH.sub.3 205-206 Colorless EtOH C.sub.17 H.sub.19      N.sub.3 O 72.57 6.81 14.93  0.87 (3H, t), 1.00˜1.95 (8H, m),      3.27(2H, t), 7.60˜7.90         72.64 6.77 14.97  (2H, m), 8.10.abou      t.8.30 (1H, m), 8.55˜8.75 (1H, m), 9.33             (1H, s) Ic-10      H H (CH.sub.2).sub.6 CH.sub.3 196-198 Colorless EtOH C.sub.10 H.sub.21      N.sub.3 O 73.19 7.17 14.23  0.87 (3H, t), 1.15˜2.00 (10H, m), 3.27      (2H, t), 7.65˜7.95         73.21 7.18 14.18  (2H, m), 8.05˜8.      30 (1H, m), 8.55˜8.80 (1H, m), 9.33             (1H, s) Ic-11 H H      (CH.sub.2).sub.7 CH.sub.3 193-195 Colorless EtOHCHCl.sub.3 C.sub.19      H.sub.23 N.sub.3 O 73.76 7.49 13.58  0.83 (3H, t), 1.05˜1.90 (12H,      m), 3.25 (2H, t), 7.65˜7.95         73.75 7.49 13.57  (2H, m),      8.05˜8.25 (1H, m), 8.55˜8.75 (1H, m), 9.33             (1H,      s) Ic-12 H H (CH.sub.2).sub.8 CH.sub.3 190-192 Colorless EtOH C.sub.20      H.sub.25 N.sub.3 O 74.27 7.79 12.99  0.83 (3H, t), 1.05˜ 1.90      (14H, m), 3.23 (2H, t), 7.65˜7.90         74.63 7.86 13.03  (2H,      m), 8.05˜8.25 (1H, m), 8.55˜8.75 (1H, m), 9.30      (1H, s) Ic-13 H H (CH.sub.2).sub.9 CH.sub.3 185-186 Colorless EtOH      C.sub.21 H.sub.27 N.sub.3       O 74.74 8.06 12.45  0.83 (3H, t,), 1.05˜1.95 (16H, m), 3.25 (2H,      t), 7.65˜         74.96 8.10 12.46  7.90 (2H, m), 8.10˜8.30      (1H, m), 8.55˜8.75 (1H, m),             9.33 (1H, s) Ic-14 H H      CH(CH.sub.3).sub.2 274-276 Colorless EtOH C.sub.14 H.sub.13 N.sub.3 O      70.26 5.48 17.56  1.27 (6H, d), 3.98 (1H, septet), 7.70˜7.90 (2H,      m), 8.05˜         70.27 5.60 17.59  8.30 (1H, m), 8.55˜8.80      (1H, m), 9.35 (1H, s) Ic-15 7-F H CH(CH.sub.3).sub.2  278-281(d)      Colorless MeOHAcOEt C.sub.14 H.sub.12 N.sub.3 OF 65.36 4.70 16.33 F 7.38      1.27 (6H, d), 3.96 (1H, septet), 7.62˜7.73 (1H, m), 7.87˜           65.33 4.74 16.25 F 7.41 7.93 (1H, m), 8.64˜8.71 (1H, m), 9.35      (1H, s) Ic-16 8-F H CH(CH.sub.3).sub.2       250-252(d) Colorless AcOEtCH.sub.2 Cl.sub.2 C.sub.14 H.sub.12 N.sub.3      OF 65.36 4.70 16.33 F 7.38 1.27 (6H, d), 3.96 (1H, septet), 7.61˜7.      71 (1H, m), 8.18˜         65.44 4.96 16.13 F 7.49 8.25 (1H, m),      8.30˜8.43 (1H, m), 9.31 (1H, s) Ic-17 8-Me H CH(CH.sub.3).sub.2      231-232 Light yellow EtOH C.sub.15 H.sub.15 N.sub.3 O 71.13 5.97 16.59      1.30 (6H, d), 3.97 (1H, septet), 7.55 (1H, d, d), 8.03         71.30      6.10 16.54  (1H, d), 8.40 (1H, d), 9.23 (1H, s)       Ic-18 H H      ##STR25##       243-244 Colorless EtOHCHCl.sub.3 C.sub.15 H.sub.16 N.sub.3 O 71.1371.09 5      .976.07 16.5916.41   0.93 (3H, t), 1.25 (3H, d), 1.40˜2.05 (2H,      m), 3.55˜4.10(1H, m), 7.65˜7.90 (2H, m), 8.10˜8.30      (1H, m), 8.60˜8.80(1H, m), 9.37 (1H, s)  Ic-19 H H CH.sub.2      CH(CH.sub.3).sub.2 259-261 Colorless EtOH C.sub.15 H.sub.15 N.sub.3 O      71.13 5.97 16.59  1.00 (6H, d), 2.33 (1H, septet), 3.15 (2H, d),      7.65˜7.90         71.32 6.10 16.49  (2H, m), 8.10˜8.30 (1H,      m), 8.55˜8.75 (1H, m), 9.33             (1H, s)  Ic-20 7-F H       ##STR26##       267-270 Colorless MeOHCHCl.sub.3 C.sub.14 H.sub.16 N.sub.3       OF 65.8765.81 3.944.13 16.4616.38 F 7.44F 7.59 1.23˜1.27 (4H, m),      3.28˜3.43 (1H, m), 7.62˜7.72 (1H, m),7.87˜7.94 (1H,      m), 8.64˜8.71 (1H, m), 9.36 (1H, s)       Ic-21 8-F H      ##STR27##       273(d) Colorless MeOHAcOEt C.sub.14 H.sub.10 N.sub.3 OF 65.8765.95      3.944.08 16.46 16.56 F 7.33F 7.32 1.24˜1.28 (4H, m), 3.30˜3.4      6 (1H, m), 7.60˜7.71 (1H, m),8.18˜8.25 (1H, m), 8.31˜8.      38 (1H, m), 9.30 (1H, s)       Ic-22 7-OMe H      ##STR28##       285(d) Colorless EtOHCHCl.sub.3 C.sub.15 H.sub.13 N.sub.3 O.sub.2      67.4167.56 4.904.95 15.7215.77  1.20 (4H, d), 3.37 (1H, quintet), 3.93      (3H, s) 7.37 (1H,d, d), 7.58 (1H, d), 8.53 (1H, d), 9.30 (1H, s)  Ic-23      8-Me H       ##STR29##       245(d) Colorless EtOH C.sub.15 H.sub.13 N.sub.3 O 71.7071.86 5.215.23      16.7216.86  1.23 (4H, d), 3.40 (1H, quintet), 3.57 (3H, s), 7.60 (1H,d,      d), 8.05 (1H, d), 8.43 (1H, d), 9.27 (1H, s)       Ic-24 H H      ##STR30##        241-243(d) Colorless EtOH C.sub.15 H.sub.12 N.sub.3 O 71.9971.96      4.835.22 16.7916.75  1.00˜1.90 (6H, m), 3.05˜3.40 (1H, m),      7.60˜7.90 (2H, m), 8.05˜8.30 (1H, m), 8.50˜8.75 (1H,      m), 9.35 (1H, s)       Ic-25 H H      ##STR31##        246-248(d) Colorless EtOH C.sub.15 H.sub.13 N.sub.3 O 71.7071.83      5.215.30 16.7216.59  1.80˜2.40 (6H, m), 4.23˜4.60 (1H, m),      7.60˜7.90 (2H, m),8.05˜8.30 (1H, m), 8.55˜8.75 (1H,      m), 9.30 (1H, s)       Ic-26 H H      ##STR32##       264(d) Colorless EtOH C.sub.16 H.sub.15 N.sub.3 O 72.4372.72 5.705.80      15.8415.79  1.50˜2.30 (8H, m), 4.00˜4.45 (1H, m), 7.65˜      7.90 (2H, m),8.10˜8.30 (1H, m), 8.55˜8.75 (1H, m), 9.35 (1H,      s)       Ic-27 H H      ##STR33##       224(d) Light yellow EtOHCHCl.sub.3 C.sub.14 H.sub.11 N.sub.3       O 70.8770.93 4.674.69 17.7117.67  2.07 (3H, d), 7.30˜7.95 (4H,      m), 8.05˜8.30 (1H, m), 8.55˜8.80 (1H, m), 9.33 (1H, s)      Ic-28 H H       ##STR34##       225-227 Colorless EtOH C.sub.14 H.sub.11 N.sub.3 O 70.8770.93 4.674.81      17.7117.48  2.10 (3H, s), 6.27˜6.40 (1H, m), 7.27 (1H, s),      7.65˜7.95(2H, m), 8.05˜8.30 (1H, m), 8.55˜8.70 (1H,      m), 9.33(1H, s)       Ic-29 H H      ##STR35##       272(d) Colorless EtOHCHCl.sub.3 C.sub.15 H.sub.13 N.sub.3 O 71.7071.87      5.215.30 16.7216.68  2.11 (3H, s), 2.35 (3H, s), 7.40˜7.50 (1H,      m), 7.60˜7.85(2H, m), 8.05˜8.25 (1H, m), 8.50˜8.75      (1H, m), 9.30(1H, s)  Ic-30 H H (CH.sub.2).sub.3 Cl 175(d) Colorless      EtOH C.sub.14 H.sub.12 N.sub.3 OCl 61.43 4.42 15.35 Cl 12.95 2.20 (2H,      t, t), 2.47 (2H, t), 2.80 (2H, t), 7.60˜7.95         61.44 4.41      15.17 Cl 13.09 (2H, m), 8.10˜8.30 (1H, m), 8.55˜8.75 (1H,      m), 9.35             (1H, s) Ic-31 H H (CH.sub.2).sub.2 SCH.sub.3 210(d)      Colorless EtOH C.sub.14 H.sub.13 N.sub.3 OS 61.97 4.83 15.49 S 11.82      2.15 (3H, s), 2.93 (2H, t), 3.57 (2H, t), 7.65˜7.90 (2H,      61.97 4.76 15.23 S 11.60 m), 8.05˜8.30 (1H, m), 8.55˜8.80      (1H, m), 9.33 (1H, s)       Ic-32 H H      ##STR36##       251-253 Colorless EtOH C.sub.19 H.sub.15 N.sub.3 O 75.7375.94 5.025.16      13.9414.02  3.07 (2H, t), 3.60 (2H, t), 7.05˜7.45 (5H, m),      7.60˜7.90(2H, m), 8.00˜8.25 (1H, m), 8.50˜8.75 (1H,      m), 9.30(1H, s)

EXAMPLE 33 2-(4-Methoxycarbonylbutylyl)-1H-imidazo[4,5-c]quinoline (I c-33) ##STR37##

To a mixture of 1.23 g of trityl compound (III-1) in 25 ml of THF and a solution of 2.5 ml of n-butyl lithium-2 ml of THF prepared in the same manner as in Example 1 was added 1.30 g of glutaric acid dimethyl ester. The mixture was stirred for 30 min. at -70° C. and 240 mg of acetic acid was added thereto. The reaction solution was elevated to room temperature and concentrated under reduced pressure. The residue obtained was distributed in ethyl acetate-saturated aqueous sodium hydrogencarbonate. The organic layer was washed with water and saturated brine, successively, and dried. The ethyl acetate was removed by evaporation, and the residue was chromatographed on a column of silica gel eluting with ethyl acetate-n-hexane (1:2 v/v) to give an oily substance (I b-33). The oily substance (I b-33) obtained was dealkylated by mixing with 4 ml of trifluoroacetic acid. After treating in the same manner as in Example 1, the residue was chromatographed on a column of silica gel for purification. The fraction eluted with chloroform-methanol (30:1 v/v) was concentrated and crystallized from n-hexane to give 245 mg (yield: 28%) of the titled compound (I c-33). This was crystallized from ethanol to give colorless crystals melting at 207°˜208° C.

Anal. Calcd. (%) for C₁₆ H₁₅ N₃ O₃ : C, 64.64; H, 5.09; N, 14.13. Found (%): C, 64.68; H, 5.09; N, 13.99.

NMR (DMSO-d₆)δ: 1.98 (2H, t, t), 2.47 (2H, t), 3.33 (2H, t), 3.63 (3H, s), 7.65˜7.90 (2H, m), 8.05˜8.25 (1H, m), 8.55˜8.75 (1H, m), 9.30 (1H, s).

EXAMPLE 34 2-Formyl-1H-imidazo[4,5-c]quinoline (I c-34) ##STR38##

To a mixture of 1.23 g of trityl compound (III-1) in 25 ml of THF and a solution of 2.5 ml of 1.6M solution of n-butyl litium in hexane -2 ml of THF prepared in the same manner as in Example 1 was added dropwise 760 mg of DMF. After stirring the reaction mixture for 30 min. at -70° C., 240 mg of acetic acid was added thereto, and the tempera-ture of the mixture was elevated to room temperature. After treating in the same manner as in Example 33, the residue was chromatographed on a column of silica gel eluting with ethyl acetate-n-hexane (1:2 v/v) to give an oily substance (I b-34). The oily substance (I b-34) obtained was dealkylated by mixing with 4 ml of trifluoroacetic acid. The reaction mixture was concentrated under reduced pressure. Saturated aqueous sodium hydrogencarbonate was added to the residue, and the resulting precipitate was collected by filtration, washed with water and dried. This was chromatographed on a column of silica gel eluting with ethyl acetate-methanol (20:3 v/v). The fraction ob-tained was concentrated and crystallized from ethanol to give 210 mg (yield: 36%) of the titled compound (I c-34). This was crystallized from DMF to give colorless crystals melting at 254° C. (d).

Anal. Calcd. (%) for C₁₁ H₇ N₃ O.1/10 H₂ O : C, 66.39; H, 3.65; N, 21.12.

Found (%): C, 66.27; H, 3.87; N, 20.86.

Mass spectrum: m/z 197 (M⁺).

NMR (DMSO-d₆)δ: 7.60˜7.95 (2H, m), 8,10˜8.30 (2H, m), 8.50˜8.70 (1H, m), 9.37 (1H, s), 10.08 (1H, s).

EXAMPLE 35 2-(4-Fluorobenzoyl)-1H-imidazo[4,5-c]quinoline (I c-35) ##STR39##

To a mixture of 1.64 g of trytyl compound (III-1) in 20 ml of THF and a solution of 4 ml of n-butyl lithium and 10 ml of THF was added 2.55 g of 4-fluorobenzoic acid chloride. The reaction solution was -10 ml of THF was added 2.55 g of 4-fluorobenzoyl chloride. The reaction mixture was warmed to room temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous ammonia. The organic layer was washed with water, then with brine and dried. The ethyl acetate was removed by evaporation and an oily substance obtained was chromatographed on a column of silica gel eluting with ethyl acetate-n-hexane (1:2 v/v). The fraction obtained was concentrated and crystallized from n-hexane to give 1.36 g of the titled compound (I b-35). The compound (I b-35) was suspended in 6 ml of trifluoroacetic acid and stirred for 30 min. at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized with saturated aqueous sodium hydrogencarbonate. The precipitate obtained was collected by filtration, washed with water and dried. This material was chromatographed on a column of silica gel eluting with chloroform-methanol (30:1 v/v) to give 740 mg (yield: 64%) of the titled compound (I c-35). This was recrystallized from ethanol-chloroform to give light yellow crystals melting at 305°˜307° C.

Anal. Calcd. (%) for C₁₇ H₁₀ N₃ OF : C, 70.10; H, 3.46; N, 14.43; F, 6.52. Found (%): C, 70.25; H, 3.70; N, 14.34; F, 6.62.

NMR (DMSO-d₆)δ: 7.30˜7.95 (4H, m), 8.10˜8.30 (1H, m), 8.57˜8.90 (3H, m), 9.40 (1H, s).

EXAMPLE 36 2-[(5-Chlorothiophen-2-yl)carbonyl]-1H-imidazo[4,5-c]quinoline (I c-36) ##STR40##

A solution of 1.4 g of methyl 5-chloro-2-thiophencarboxylate in 2 ml of THF was added dropwise to a solution prepared in the same manner as in Example 1 from a solution of 1.23 g of the compound (III-1) in 25 ml of THF and a mixture of 2.5 ml of 1.6M solution of n-butyl lithium in hexane -2 ml of THF. After stirring for 30 min., 240 mg of acetic acid was added thereto, and the temperature was elevated to room temperature. After workup in the same manner as in Example 33, the residue was chromatographed on a column of silica gel eluting with ethyl acetate-n-hexane (1:2 v/v). The fraction was concentrated to give an oily substance (I b-36). The oily substance (I b-36) was dealkylated by mixing with 4 ml of trifluoroacetic acid. Crude crystals obtained by the same workup as in Example 35 were chromatographed on a column of silica gel for purification. When the fraction eluted with chloroform-methanol (30:1 v/v) was concentrated and crystallized from ethanol, 560 mg (yield: 61%) of the titled compound (I c-36) was obtained. This was recrystallized from ethanol-chloroform to give light yellow crystals melting at 320°-322° C.

Anal. Calcd. (%) for C₁₅ H₈ N₃ OSCl :C, 57.42; H, 2.57; N, 13.39; S, 10.22; Cl, 11.30. Found (%): C, 57.17; H, 2.77; N, 13.17; S, 10.17; Cl, 11.24.

NMR (DMSO-d₆)δ: 7.38 (1H, d), 7.60˜7.90 (2H, m), 8.05˜8.25 (1H, m), 8.53 (1H, d), 8.55˜8.80 (1H, m), 9.33 (1H, s).

EXAMPLES 37˜63

In the same manner as in Examples 35 or 36, the objective compounds (I c) were obtained under the reaction conditions shown in Table 3. The physical properties of the compounds were shown in Tables 4-1 and 4-2.

                                      TABLE 3                                      __________________________________________________________________________      ##STR41##                                                                      ##STR42##                                                                                   1st Step                                                                       Amount of                             Compound (Ic)                            Compd.                          2nd Step                                                                             Yield from                 Ex            (III-1)                                                                              Solvent                                                                              n-BuLi-THF                                                                             RCOX  Solvent                                                                              CF.sub.3 CO.sub.2 H                                                                  (III-1)                                                                              Compd.               No                                                                               R           (g)   THF (ml)                                                                             (ml)                                                                               (ml)                                                                               X  (g)                                                                               THF (ml)                                                                             (ml)  (mg)                                                                              (%)                                                                               No.                  __________________________________________________________________________     37                                                                                ##STR43##  1.23  30    3   3   Cl 1.59                                                                              --    5     370                                                                               43 Ic-37                38                                                                                ##STR44##  1.23  25    3   3   Cl 1.56                                                                              --    4     450                                                                               52 Ic-38                39                                                                                ##STR45##  1.23  25    2.5 2   Cl 1.44                                                                              --    4     350                                                                               38 Ic-39                40                                                                                ##STR46##  1.23  30    4   4   Cl 2.60                                                                              --    10    545                                                                               53 Ic-40                41                                                                                ##STR47##  0.82  20    3   3   Cl 1.77                                                                              --    5     180                                                                               29 Ic-41                42                                                                                ##STR48##  1.23  25    4   4   Cl 2.35                                                                              --    5     295                                                                               32 Ic-42                43                                                                                ##STR49##  1.23  25    2.5 2   Cl 1.50                                                                              --    4     460                                                                               50 Ic-43                44                                                                                ##STR50##  1.23  25    4   4   Cl 2.20                                                                              --    6     600                                                                               66 Ic-44                45                                                                                ##STR51##  1.23  25    2.5 2   OMe                                                                               1.32                                                                              4 ml  4     560                                                                               59 Ic-45                46                                                                                ##STR52##  1.23  25    4   4   Cl 1.99                                                                              --    6     410                                                                               48 Ic-46                47                                                                                ##STR53##  1.23  25    2.5 2   Cl 1.29                                                                              --    4     520                                                                               61 Ic-47                48                                                                                ##STR54##  1.23  25    2.5 2   OEt                                                                               1.20                                                                              --    4     420                                                                               51 Ic-48                49                                                                                ##STR55##  1.23  25    2.5 2   OEt                                                                               1.30                                                                              2 ml  4     300                                                                               37 Ic-49                50                                                                                ##STR56##  1.23  25    4   4   OEt                                                                               1.98                                                                              --    5     300                                                                               36 Ic-50                51                                                                                ##STR57##  1.23  25    2   2   Cl 0.70                                                                              2 ml  4     310                                                                               37 Ic-51                52                                                                                ##STR58##  1.23  25    2.5 2   OMe                                                                               1.40                                                                              2 ml  2     100                                                                               11 Ic-52                53                                                                                ##STR59##  1.23  25    2.5 2   OMe                                                                               1.25                                                                              2 ml  4     430                                                                               49 Ic-53                54                                                                                ##STR60##  1.23  25    2.5 2   OMe                                                                               1.25                                                                              2 ml  8     500                                                                               57 Ic-54                55                                                                                ##STR61##  1.23  25    2.5 2   Cl 1.30                                                                              --    4     530                                                                               60 Ic-55                56                                                                                ##STR62##  1.23  25    2.5 2   Cl 1.06                                                                              --    5     415                                                                               53 Ic-56                57                                                                                ##STR63##  1.23  25    2.5 2   OMe                                                                               1.15                                                                              --    4     425                                                                               51 Ic-57                58                                                                                ##STR64##  1.23  25    2.5 2   Cl 1.04                                                                              --    4     485                                                                               62 Ic-58                59                                                                                ##STR65##  1.95  30    3   3   Cl 1.26                                                                              --    4     115                                                                                9 Ic-59                60                                                                                ##STR66##  1.23  25    3   3   Cl 1.40                                                                              --    6     470                                                                               57 Ic-60                61                                                                                ##STR67##  1.23  25    2.5 2   Cl 1.40                                                                              4 ml  4     140                                                                               17 Ic-61                62                                                                                ##STR68##  1.23  25    2   2   OEt                                                                               1.00                                                                              2 ml  2     220                                                                               26 Ic-62                63                                                                                ##STR69##  1.23  25    2.5 2   OEt                                                                               1.40                                                                              2 ml  4     220                                                                               25 Ic-63                __________________________________________________________________________

    TABLE 4       ##STR70##              Elementary Analysis (%)  Compd.  m.p.  Recrystalli- Molecular Up      (Calcd.) Down (Found) No. R (°C.) Appearance zing Solvent Formula C       H N  NMR (DMSO-d.sub.6) δ                   Ic-37       ##STR71##       263-265 Lightyellow EtOH C.sub.17 H.sub.10 N.sub.3 OF 70.1069.85      3.463.68 14.4314.38 F 6.52F 6.64 7.30˜7.97 (5H,m), 8.00˜8.33      (2H,m), 8.53˜8.80 (1H,m),9.37 (1H,s)       Ic-38      ##STR72##       306-308 Lightyellow EtOH CHCl.sub.3 C.sub.17 H.sub.10 N.sub.3 OF      70.1070.20 3.463.76 14.4314.41 F 6.52F 6.58 7.55˜7.95 (4H,m),      8.07˜8.27 (1H,m), 8.30˜8.53 (2H,m),8.60˜8.80 (1H,m),      9.40 (1H,s)       Ic-39      ##STR73##         287-289(d) Lightyellow EtOHCHCl.sub.3 C.sub.17 H.sub.9 N.sub.3      OF.sub.2 66.0266.03 2.933.16 13.5913.55 F 12.29F 12.26 7.20˜7.90      (4H,m), 8.10˜8.45 (2H,m), 8.55˜8.85 (1H,m),9.33 (1H,s)      Ic-40       ##STR74##       252-253 Colorless EtOHCHCl.sub.3 C.sub.18 H.sub.10 N.sub.3 OF.sub.3      63.8563.50 2.953.07 12.3112.37 F 16.70F 16.45 7.70˜8.30 (5H,m),      8.60˜8.80 (1H,m), 8.83˜9.03 (2H,m),9.40 (1H,s)  Ic-41       ##STR75##       310(s) Yellow EtOHCHCl.sub.3 C.sub.17 H.sub.10 N.sub.3 OCl 66.3566.61      3.28 3.29 13.6513.66 Cl 11.52Cl 11.33 7.60˜7.90 (4H,m), 8.05˜      8.25 (1H,m), 8.55˜8.80 (3H,m),9.37 (1H,s)       Ic-42      ##STR76##         298-300(d) Lightyellow EtOHCHCl.sub.3 C.sub.17 H.sub.10 N.sub.3 OCl      66.3566.04 3.283.58 13.6513.35 Cl 11.52Cl 11.42 7.50˜8.00 (6H,m),      8.15˜8.30 (1H,m), 8.50˜8.80 (1H,m),9.33 (1H,s)  Ic-43       ##STR77##       283-285 Lightyellow EtOHCHCl.sub.3 C.sub.17 H.sub.10 N.sub.3 OCl      66.3566.43 3.283.34 13.6513.65 Cl 11.52Cl 11.82 7.60˜7.95 (4H,m),      8.10˜8.35 (1H,m), 8.50˜8.80 (3H,m),9.40 (1H,s)  Ic-44       ##STR78##       274-276 Colorless EtOH C.sub.18 H.sub.13 N.sub.3 O.sub.2 71.2871.39     4      4.32.30 13.8513.79  3.93 (3H,s), 7.20 (2H,d), 7.65˜7.93 (2H,m),      8.05˜8.30(1H,m), 8.60˜8.85 (3H,m), 9.40 (1H,s)  Ic-45       ##STR79##       275-277 Lightyellow EtOHCHCl.sub.3 C.sub.18 H.sub.13 N.sub.3 OS      67.6967.88 4.104.26 13.1613.06 S 10.04S  9.92 2.60 (3H,s), 7.47 (2H,d),      7.65˜7.90 (2H,m), 8.10˜8.30(1H,m), 8.55˜8.80 (3H,m),      9.37 (1H,s)       Ic-46      ##STR80##       286-287 Lightyellow EtOHCHCl.sub.3 C.sub.18 H.sub.13 N.sub.3       O 75.2575.17 4.564.59 14.6214.52  2.45 (3H,s), 7.45 (2H,d), 7.65˜7      .90 (2H,m), 8.07˜8.30(1H,m), 8.50˜8.80 (3H,m), 9.37 (1H,s)      Ic-47       ##STR81##       246-248 Colorless EtOH C.sub.18 H.sub.13 N.sub.3 O 75.2575.72 4.564.83      14.6214.57  2.47 (3H,s), 7.45˜7.90 (4H,m), 8.05˜8.80 (4H,m),      9.40(1H,s)       Ic-48      ##STR82##       311-312 Yellow EtOHCHCl.sub.3 C.sub.16 H.sub.10 N.sub.4 O 70.0770.02      3.683.86 20.4320.22  7.65˜7.90 (2H,m), 8.10˜8.30 (1H,m),      8.33˜8.47 (2H,m),8.60˜8.80 (1H,m), 8.90˜9.05 (2H,m),      9.40 (1H,s)       Ic-49      ##STR83##         330-333(d) Yellow EtOHCHCl.sub.3 C.sub.16 H.sub.10 N.sub.4       O 70.0770.36 3.683.91 20.4320.39  7.60˜7.90 (3H,m), 8.10˜8.2      5 (1H,m), 8.65˜9.00 (3H,m),9.40 (1H,s), 9.63˜9.80 (1H,m)      Ic-50       ##STR84##         315-317(d) Colorless EtOHCHCl.sub.3 C.sub.15 H.sub.9 N.sub.3 OS      64.5064.36 3.253.38 15.0414.81 S 11.48S 11.27 7.30˜7.45 (1H,m),      7.60˜7.90 (2H,m), 8.05˜8.33 (2H,m),8.55˜8.90 (2H,m),      9.37 (1H,s)       Ic-51      ##STR85##       300-302 Yellow EtOHCHCl.sub.3 C.sub.15 H.sub.9 N.sub.3 OS 64.5064.50      3.253.43 15.0414.99 S 11.48S 11.39 7.65˜7.90 (3H,m), 7.95˜      8.30 (2H,m), 8.63˜8.80 (1H,m),9.37 (1H,s), 9.40˜9.50 (1H,m)      Ic-52       ##STR86##       335(d) Yellow DMF C.sub.15 H.sub.8 N.sub.3 OSCl 57.4257.29 2.572.83      13.3913.41 S 10.22,Cl 11.30S 10.26,Cl 11.44 7.65˜7.90 (2H,m), 7.97      (1H,d), 8.05˜8.30 (1H,m), 8.65˜8.80 (1H,m), 9.25 (1H,d),      9.35 (1H,s)       Ic-53      ##STR87##         320-323(d) Yellow EtOHCHCl.sub.3 C.sub.16 H.sub.11 N.sub.3 OS      65.5165.58 3.783.87 14.3214.32 S 10.93S 10.79 2.60 (3H,s), 7.13 (1H,d),      7.65˜7.85 (2H,m), 8.05˜8.30(1H,m), 8.60˜8.80 (2H,m),      9.35 (1H,s)       Ic-54      ##STR88##         306-308(d) Yellow EtOHCHCl.sub.3 C.sub.16 H.sub.11 N.sub.3 OS      65.5165.46 3.783.96 14.3214.24 S 10.93S 10.96 2.37 (3H,s), 7.65˜7.9      0 (3H,m), 8.10˜8.30 (1H,m), 8.60˜8.80 (2H,m), 9.40 (1H,s)      Ic-55       ##STR89##       291(d) Yellow EtOHCHCl.sub.3 C.sub.16 H.sub.11 N.sub.3 OS 65.5165.19      3.783.89 14.3214.03 S 10.93S 10.85 2.70 (3H,s), 7.20 (1H,d), 7.65˜7      .90 (2H,m), 8.05˜8.30(1H,m), 8.07 (1H,d), 8.60˜8.80 (1H,m),      9.37 (1H,s)       Ic-56      ##STR90##         305-307(d) Yellow EtOHCHCl.sub.3 C.sub.16 H.sub.9 N.sub.3 O.sub.2      68.4468.56 3.453.51 15.9616.07  6.83˜6.97 (1H,m), 7.63˜7.90      (2H,m), 8.10˜8.30 (2H,m),8.50 (1H,d), 8.60˜8.77 (1H,m), 9.37      (1H,s)       Ic-57      ##STR91##         316-318(d) Yellow EtOHCHCl.sub.3 C.sub.16 H.sub.11 N.sub.3 O.sub.2      69.3169.31 4.003.94 15.1515.16  2.47 (3H,s), 6.57 (1H,d), 7.65˜7.90       (2H,m), 8.10˜8.30(1H,m), 8.45 (1H,d), 8.60˜8.80 (1H,m),      9.35 (1H,s)       Ic-58      ##STR92##         295-297(d) Colorless EtOH C.sub.15 H.sub.9 N.sub.3 O.sub.2 68.4468.73 3      .453.63 15.9616.05  7.23 (1H,d), 7.65˜7.90 (2H,m), 7.97 (1H,m),      8.05˜8.30(1H,m), 8.60˜8.85 (1H,m), 9.30 (1H,d), 9.37 (1H,s)      Ic-59       ##STR93##         263-265(d) Yellow EtOH C.sub.14 H.sub.8 N.sub.4 O.sub.2 63.6363.74      3.053.23 21.2020.96  7.57 (1H,d), 7.70˜7.90 (2H,m), 8.10˜8.30       (1H,m), 8.60˜8.80 (1H,m), 7.30 (1H,d), 7.40 (1H,s)  Ic-60       ##STR94##         276-278(d) Yellow EtOHCHCl.sub.3 C.sub.15 H.sub.10 N.sub.4 O.sub.2      64.7464.98 3.623.78 20.1319.97  2.59 (3H,s), 7.23 (1H,s), 7.60˜7.90       (2H,m), 8.05˜8.30(1H,m), 8.55˜8.75 (1H,m), 9.37 (1H,s)      Ic-61       ##STR95##       330(d) Yellow EtOHCHCl.sub.3 C.sub.15 H.sub.10 N.sub.4       O.sub.2 64.7464.65 3.623.60 20.1319.97  *Not measured, as it was      difficult to dissolve the compound       Ic-62      ##STR96##         291-293(d) Lightyellow EtOHCHCl.sub.3 C.sub.15 H.sub.10 N.sub.4      O.sub.2 64.7465.05 3.623.75 20.1319.79  2.53 (3H,s), 7.65˜7.85      (2H,m), 8.05˜8.25 (1H,m), 8.55˜8.80 (1H,m), 9.31 (1H,s),      9.47 (1H,s)       Ic-63      ##STR97##       325(d) Lightyellow MeOHCHCl.sub.3 C.sub.15 H.sub.10 N.sub.4       OS 61.2161.29 3.423.62 19.0418.71 S 10.89S 10.69 *Measuring solvent      CDCl.sub.3CD.sub.3       OD,2.85 (3H,s), 8.65˜8.90 (2H,m), 8.10˜8.30 (1H,m),8.40.abou      t.8.60 (1H,m), 9.30 (1H,s), 9.55 (1H,s)

EXAMPLE 64 2-Benzoyl-8-fluoro-1H-imidazo[4,5-c]quinoline (I d-1) ##STR98##

To a suspension of 830 mg of 2-benzyl-8-fluoro-1H-imidazo[4,5-c]-quinoline (VII-1) in 50 ml of dioxane heated to 80° C. was added 1.07 g of selenium dioxide. The reaction mixture was refluxed for 1.5 hours. The resulting precipitate was immediately removed by filtration and concentrated under reduced pressure, and the residue obtained was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with water and saturated brine, and dried. The ethyl acetate was removed and the residue was chromatographed on a column of silica gel for purification. After elution with chloroform-methanol (30:1 v/v), 820 mg (yield 94%) of the compound (I d-1) was obtained as crystals. This was recrystallized from ethanol-chloroform to give light yellow crystals melting at 255°˜256° C.

Anal. Calcd. (%) for C₁₇ H₁₀ N₃ OF : C, 70.10; H, 3.46; N, 14.43; F, 6.52. Found (%): C, 70.22; H, 3.57; N, 14.43; F, 6.64.

NMR (DMSO-d₆)δ: 7.50˜7.90 (4H, m), 8.07˜8.47 (2H, m), 8.53˜8.75 (2H, m), 9.31 (1H, s).

EXAMPLES 65˜67

In the same manner as in Example 64, the objective compounds (I d) were obtained under the reaction conditions shown in Table 5. The physical properties of the compounds were shown in Tables 6-1 and 6-2.

                                      TABLE 5                                      __________________________________________________________________________      ##STR99##                                                                     Amount of         Selenium    Reflux                                                                             Compound (Id)                                Ex.   Compound (VII)                                                                             dioxide                                                                             Dioxane                                                                               Time                                                                               Yield   Compd.                               No.   R.sup.1                                                                             R.sup.2                                                                          (mg) (mg) (ml)   (hr)                                                                               (mg) (%)                                                                               No.                                  __________________________________________________________________________     65    H    H 300  420  20     1   285  90 Id-2                                 66    7-F  H 700  1000 40     2   270  37 Id-3                                 67    7-OMe                                                                               H 500  615  30     1   335  64 Id-4                                 __________________________________________________________________________

                                      TABLE 6                                      __________________________________________________________________________      ##STR100##                                                                                                              Elementary                                                                     Analysis (%)                                                    Solvent        Up (Calcd.),                         Compd.          m.p.  Appear-                                                                             for Re- Molecular                                                                             Down (Found)                         No.  R    R.sup.1                                                                            R.sup.2                                                                          (°C.)                                                                         ance crystalln.                                                                             Formula                                                                               C  H  N     NMR (DMSO-d.sub.6),                                                            δ                  __________________________________________________________________________     Id-2                                                                                 ##STR101##                                                                         H   H 285-287                                                                              Color- less                                                                         EtOH    C.sub.17 H.sub.11 N.sub.3 O                                                           74.71 74.85                                                                       4.06 4.16                                                                         15.38 15.22                                                                          7.53˜7.90                                                                (5H,m), 8.17˜8                                                           .27 (1H,m),                                                                    8.53˜8.70                                                                (3H,m), 9.37                                                                   (1H,s)                   Id-3                                                                                 ##STR102##                                                                         7-F H 318-320(d)                                                                           Light yellow                                                                        EtOHCHCl.sub.3                                                                         C.sub.17 H.sub.10 N.sub.3 OF                                                          70.10 70.21                                                                       3.46 3.53                                                                         14.43 14.45                                                                       F 6.52 F 6.55                                                                     7.50˜7.97                                                                (5H,m), 8.53˜8                                                           .85 (3H,m), 9.37                                                               (1H,s)                   Id-4                                                                                 ##STR103##                                                                         7-OMe                                                                              H 322-324(d)                                                                           Color- less                                                                         EtOHCHCl.sub.3                                                                         C.sub.18 H.sub.13 N.sub.3 O.sub.2                                                     71.28 71.36                                                                       4.32 4.25                                                                         13.85 13.61                                                                          3.95 (3H,s),                                                                   7.30˜7.90                                                                (5H,m), 8.47˜8                                                           .80 (3H,m), 9.33                                                               (1H,s)                   __________________________________________________________________________

EXAMPLE 68 2-Ethoxycarbonyl-1H-imidazo[4,5-c]quinoline (I c-64) ##STR104##

To a solution prepared in the same manner as in Example 1 from 410 mg of the compound (III-1) in 5 ml of THF and a mixture of 1 ml of 1.6M solution of n-butyl lithium in hexane-5 ml of THF was added 350 mg of ethyl chloroformate. The reaction mixture was warmed to room temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with water and saturated brine, and dried. After evaporating the ethyl acetate, the residue was crystallized from n-hexane to give 455 mg of the compound (I b-64) as crude crystals. The compound (I b-64) was dealkylated by mixing with 4 ml of trifluoroacetic acid. After treatment in the same manner as in Example 1, the crude product was chromatographed on a column of silica gel for purification. After elution with chloroform-methanol (10:1 v/v) and evaporation of the fraction obtained, the residue was crystallized from n-hexane to give 200 mg (yield: 83%) of the titled compound (I c-64). This was recrytallized from ethyl acetate to give colorless crystals melting at 198°˜200° C.

Anal. Calcd. (%) for C₁₃ H₁₁ N₃ O₂ : C, 64.72; H, 4.60; N, 17.42. Found (%): C, 64.74; H, 4.58; N, 17.43.

NMR (DMSO-d₆)δ: 1.42 (3H, t), 4.50 (2H, q), 7.60˜7.90 (2H, m), 8.05˜8.30 (1H, m), 8.55˜8.75 (1H, m), 9.33 (1H, s).

EXAMPLE 69 2-Isopropyloxycarbonyl-1H-imidazo[4,5-c]quinoline (I c-65) ##STR105##

In the same manner as in Example 68, isopropyl chloroformate was allowed to react with III-1 to give the titled compound (I c-65) in 50 % yield. This was crystallized from ethyl acetate to give colorless crystals melting at 245°˜247° C.

Anal. Calcd. (%) for C₁₄ H₁₃ N₃ O₂ : C, 65.87; H, 5.13; N, 16.46. Found (%): C, 65.80; H, 5.24; N, 16.42.

NMR (DMSO-d₆)δ: 1.43 (6H, d), 5.30 (1H, septet), 7.60˜7.85 (2H, m), 8.05˜8.25 (1H, m), 8.50˜8.70 (1H, m), 9.30 (1H, s).

EXAMPLE 70 2-Ethoxycarbonyl-7-fluoro-1H-imidazo[4,5-c]quinoline (I e-1) ##STR106##

A solution of 1.15 g of 4-amino-7-fluoro-3-(trichloroacetimidoylamino)quinoline diacetate (VIII-1) in 120 ml of ethanol was heated under reflux for two hours. The reaction mixture was concentrated under reduced pressure, and the residue was added to ice-water. After being basified with 2N aqueous ammonia, the mixture was extracted with chloroform. The extract was washed with water and brine, and then dried. The chloroform was removed by evaporation. The residue was chromatographed on a column of silica gel with chloroform-methanol (100:1 v/v), whereby 395 mg (yield: 59%) of the titled compound (I e-1) was obtained as crystals. These were recrystallized from chloroform-ethanol to give colorless crystals melting at 238°˜240° C. (d).

Anal. Calcd. (%) for C₁₃ H₁₀ N₃ O₂ F: C, 60.23; H, 3.89; N, 16.21; F, 7.33. Found (%): C, 60.16; H, 4.03; N, 16.29; F, 7.41.

NMR (DMSO-d₆)δ: 1.41 (3H, t), 4.49 (2H, q), 7.50˜8.10 (2H, m), 8.60˜8.80 (1H, m), 9.33 (1H, s).

EXAMPLES 71˜72

In the same manner as in Example 70, the objective compounds (Ie) were obtained under reaction conditions shown in Table 7. The physical properties of the compounds were shown in Tables 8-1 and 8-2.

                                      TABLE 7                                      __________________________________________________________________________      ##STR107##                                                                              Amount   Reaction                                                                            Reaction                                                                            Compound (Ie)                                     Ex.       of VIII                                                                             R.sup.3 OH                                                                         Temp.                                                                               Time Yield Compd.                                      No.                                                                               R.sup.3                                                                               (mg) (ml)                                                                               (°C.)                                                                        (hr) (mg)                                                                              (%)                                                                               No.                                         __________________________________________________________________________     71 CH.sub.3                                                                              800  20  Reflux                                                                              16   234                                                                               47 Ie-2                                        72 (CH.sub.2).sub.2 CH.sub.3                                                             182  20  80    4    68                                                                               53 Ie-3                                        __________________________________________________________________________

                                      TABLE 8                                      __________________________________________________________________________      ##STR108##                                                 (Ie)                                      Solvent        Elementary Analysis                                         ap- for            (%) Up (Calcd.), Down                    Compd.      m.p.   pear-                                                                              recrysta-                                                                              Molecular                                                                             (Found)                                  No.  R.sup.3                                                                               (°C.)                                                                          ance                                                                               lln.    Formula                                                                               C   H   N   NMR (DMSO-d.sub.6),                                                            δ                      __________________________________________________________________________     Ie-2 CH.sub.3                                                                              218-219(d)                                                                            Color-                                                                             EtOHCHCl.sub.3                                                                         C.sub.12 H.sub.9 N.sub.3 O.sub.2                                                      63.42                                                                              3.99                                                                               18.49                                                                              4.00(3H, s),                                                                   7.60˜8.70                                 less               63.14                                                                              3.99                                                                               18.21                                                                              (4H, m), 9.27(1H, s)         Ie-3 (CH.sub.2).sub.2 CH.sub.3                                                             214-217                                                                               Color-                                                                             EtOHCHCl.sub.3                                                                         C.sub.14 H.sub.13 N.sub.3 O.sub.2                                                     65.87                                                                              5.13                                                                               16.46                                                                              1.00(3H, t), 1.80(2H,                                                          m),                                             less               65.43                                                                              5.21                                                                               16.50                                                                              4.37(2H, t),                                                                   7.60˜8.80                                                                (4H, m), 9.27(1H,            __________________________________________________________________________                                                       s)                      

EXAMPLE 73 2-Methylcarbamoyl-1H-imidazo[4,5-c]quinoline (Ic-66) ##STR109##

To a solution prepared in the same manner as in Example 1 from 1.23 g of the compound (III-1) in 30 ml of THF and a mixture of 4 ml of 1.6M solution of n-butyl lithium in hexane-4 ml of THF was added 770 mg of methyl isocyanate. The reaction mixture was gradually warmed to room temperature and concentrated under reduced pressure. Water was added to the residue, and the product was extracted with ethyl acetate. The extract was washed with water and brine, and then dried. The ethyl acetate was removed and the residue was crystallized from ether to give 990 mg of the compound (Ib-66) as crude crystals. The compound (Ib-66) was dealkylated by mixing with 4 ml of trifluoroacetic acid and stirred for 30 min. at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized with saturated aqueous sodium hydrogencarbonate. The crystals precipitated were collected by filtration, washed with water and ethanol, and then dried to give 410 mg (yield: 61%) of the titled compound (Ic-66). The compound (Ic-66) was recrystallized from ethanol-chloroform to give colorless crystals, m.p. at 322° C. (s).

Anal Calcd. (%) for C₁₂ H₁₀ N₄ C: C, 63.71; H, 4.46; N, 24.76. Found (%): C, 63.60; H, 4.60; N, 24.48.

NMR (DMSO-d₆ -CD₃ OD)δ: 3.93 (3H, s), 7.57˜7.90 (2H, m), 8.07˜8.30 (1H, m), 8.55˜8.80 (1H, m), 9.27 (1H, s).

EXAMPLES 74˜76

In the same manner as in Example 73, the objective compounds (Ic) were obtained under the reaction conditions shown in Table 9. The physical properties of the compounds were shown in Tables 10-1 and 10-2.

                                      TABLE 9                                      __________________________________________________________________________      ##STR110##                                                                     ##STR111##                                                                              1st Step                 2nd Step                                                                             Compound (Ic)                         Ex.       Amount of                                                                            Solvent                                                                              n-BuLiTHF                                                                              R.sup.4 NCO                                                                         CF.sub.3 CO.sub.2 H                                                                  Yield Compd.                          No.                                                                               R.sup.4                                                                               III-1 (g)                                                                            THF (ml)                                                                             (ml)                                                                               (ml)                                                                               (g)  (ml)  (mg)                                                                              (%)                                                                               No.                             __________________________________________________________________________     74 C.sub.2 H.sub.5                                                                       1.23  25    2.5 2   0.63 4     300                                                                               42 Ic-67                           75 (CH.sub.2).sub.2 CH.sub.3                                                             1.23  25    2.5 2   0.68 3     260                                                                               34 Ic-68                           76 CH(CH.sub.3).sub.2                                                                    1.23  25    2.5 2   0.69 4     540                                                                               71 Ic-69                           __________________________________________________________________________

                                      TABLE 10                                     __________________________________________________________________________      ##STR112##                                    (Ic)                            __________________________________________________________________________                           Solvent       Elementary Analysis (%)                                          for           Up (Calcd.),                               Compd.      m.p. Appear-                                                                             Recrys- Molecular                                                                            Down (Found)                               No.  R.sup.4                                                                               (°C.)                                                                        ance talln.  Formula                                                                              C    H   N                                 __________________________________________________________________________     Ic-67                                                                               C.sub.2 H.sub.5                                                                       296-297                                                                             Colorless                                                                           EtOHCHCl.sub.3                                                                         C.sub.13 H.sub.12 N.sub.4 O                                                          64.99                                                                               5.03                                                                               23.32                                                                 64.92                                                                               5.23                                                                               23.19                             Ic-68                                                                               (CH.sub.2).sub.2 CH.sub.3                                                             253-254                                                                             Colorless                                                                           EtOH    C.sub.14 H.sub.14 N.sub.4 O                                                          66.13                                                                               5.55                                                                               22.03                                                                 66.12                                                                               5.47                                                                               21.92                             Ic-69                                                                               CH(CH.sub.3).sub.2                                                                    263-264                                                                             Colorless                                                                           EtOH    C.sub.14 H.sub.14 N.sub.4 O                                                          66.13                                                                               5.55                                                                               22.03                                                                 66.08                                                                               5.57                                                                               21.96                             __________________________________________________________________________                     Compound                                                                       No.   NMR (DMSO-d.sub.6 ) δ                              __________________________________________________________________________                     Ic-67 1.17 (3H,t), 3.20˜3.57 (2H,m),                                           7.60˜7.90 (2H,m), 8.05˜8.30                                        (1H,m), 8.55˜8.80 (1H,m), 9.13 (1H,t), 9.37                              (1H,s)                                                                   Ic-68 0.93 (3H,t), 1.65 (2H,t,q), 3.35 (2H,d,t),                                     7.60˜7.90 (2H,                                                           m), 8,10˜8.30 (1H,m), 8.55˜8.80 (1H,m),                            9.10 (1H,t), 9.30                                                              (1H,s)                                                                   Ic-69 1.27 (6H,d), 4.05˜4.45 (1H,m),                                           7.65˜7.90 (2H,m), 8.10˜8.30                                        (1H,m), 8.10˜8.30 (1H,m), 8.55˜8.75                                (1H,m), 8.87 (1H,d),                                                           9.30 (1H,s)                                              __________________________________________________________________________

EXAMPLE 77 2-Carbamoyl-1H-imidazo[4,5-c]quinoline (Ig-1) ##STR113##

A mixture of 30 ml of 28% aqueous ammonia and 1.00 g of the compound (Ic-64) was heated at 100° C. for two hours in a sealed tube. The reaction mixture was concentrated to 20 ml of the volume, and the resulting crystals were washed successively with water, ethanol, and n-hexane, whereby 688 mg (yield: 74%) of the titled compound (Ig-1) was obtained. This was recrystallized from methanol-chloroform to give colorless crystals, m.p. 326°˜328° C.

Anal. Calcd. (%) for C₁₁ H₈ N₄ O.2/3H₂ O: C, 58.92; H, 4.20; N, 24.99. Found (%): C, 58.95; H, 4.02; N, 24.95.

Mass spectrum: m/z, 212 (M⁺).

NMR (DMSO-d₆ -CD₃ OD)δ: 7.55˜7.85 (2H, m), 8.05˜8.25 (1H, m), 8.55˜8.75 (1H, m), 9.23 (1H, s).

EXAMPLE 78 2-Diethylcarbamoyl-1H-imidazo[4,5-c]quinoline (Ig-2) ##STR114##

To a solution of 560 mg of the compound (Ic-64) in 10 ml of ethanol was added 4.8 ml of 1N aqueous sodium hydroxide, and the mixture was refluxed for one hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 10 ml of water, and acidified with 5.2 ml of 1N aqueous hydrochloric acid. The precipitated crystals were collected by filtration, washed with water and dried, whereby 440 mg of carboxylic acid were obtained as crude crystals. These were suspended in 8 ml of thionyl chloride, and the suspension was refluxed for 30 min. The excess thionyl chloride was evaporated under reduced pressure, and 10 ml of toluene was added to the residue. After stirring the mixture, the toluene was evaporated under reduced pressure. To a suspension of the resulting residue in 10 ml of dichloromethane was added 2 ml of diethylamine at room temperature, and the mixture was stirred vigorously for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and then dried. The ethyl acetate was removed and the residue was chromatographed on a column of silica gel for purification. The fraction eluted with chloroform-methanol (10:1 v/v) was concentrated and the residue was crystallized from n-hexane to give 110 mg (yield: 10%) of the titled compound (Ig-2). This was recrystallized from ethyl acetate-n-hexane to give colorless crystals melting at 179°˜181° C.

Anal. Calcd. (%) for C₁₅ H₁₆ N₄ O: C, 67.15; H, 6.01; N, 20.88. Found (%): C, 67.05; H, 6.00; N, 20.52.

NMR (DMSO-d₆), δ: 1.23 (3H, t), 1.31 (3H, t), 3.57 (2H, q), 4.13 (2H, q), 7.60˜7.90 (2H, m), 8.03˜8.30 (1H, m), 8.53˜8.80 (1H, m), 9.29 (1H, s).

EXAMPLE 79 2-Dimethylcarbamoyl-1H-imidazo[4,5-c]quinoline (Ic-70) ##STR115##

In the same manner as in Ex. 1, to a solution containing 1.23 g of the compound (III-1) in 25 ml of THF and a mixture of 2.5 ml of 1.6M solution of n-butyl lithium in hexane-2 ml of THF was added 930 mg of dimethylcarbamoyl chloride, and the usual workup gave 610 mg of the compound (Ib-70) as crude crystals. The compound (Ib-70) was dealkylated by mixing with 3 ml of trifluoroacetic acid. The crude crystals were chromatographed on a column of silica gel with chloroform-methanol (30:1 v/v), whereby 280 mg (yield: 30%) of the titled compound (Ic-70) was obtained. This was recrystallized from ethanol to give colorless crystals, m.p. 284°˜286° C.

Anal. Calcd. (%) for C₁₃ H₁₂ N₄ O: C, 64.99; H, 5.03; N, 23.32. Found (%): C, 65.17; H, 5.15; N, 23.25.

NMR (DMSO-d₆), δ: 3.15 (3H, s), 3.67 (3H, s), 7.60˜7.90 (2H, m), 8.05˜8.25 (1H, m), 8.55˜8.75 (1H, m), 9.27 (1H, s).

EXAMPLE 80 2-Carboxy-1H-imidazo[4,5-c]quinoline (If-1) ##STR116##

To a solution of 240 mg of the compound (Ic-64) in 4 ml of ethanol was added 2 ml of 1N aqueous sodium hydroxide, and the mixture was refluxed for one hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 5 ml of water, and acidified with 2.2 ml of 1N aqueous hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and dried at room temperature under reduced pressure to give 200 mg (yield: 94%) of the titled compound (If-1).

Melting point: 165°˜167° C. (d).

Anal. Calcd. (%) for C₁₁ H₇ N₃ O₂ : C, 61.97; H, 3.31; N, 19.71. Found (%): C, 61.88; H, 3.51; N, 19.65.

NMR (DMSO-d₆)δ: 7.55˜7.95 (2H, m), 8.05˜8.35 (1H, m), 8.50˜8.85 (1H, m), 9.30 (1H, s).

EXAMPLE 81 2-Cyclopropylcarbonyl-1-methyl-1H-imidazo[4,5-c]quinoline (Ia-1) ##STR117##

In the same manner as in Ex. 1, to a solution containing 550 mg of 1-methyl-1H-imidazo[4,5-c]quinoline (II-2) in 25 ml of THF and a mixture of 2.2 ml of 1.6M solution of n-butyl lithium in hexane-2 ml of THF was added 0.75 g of cyclopropanecarbonyl chloride. The reaction mixture was gradually warmed to room temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous ammonia. The organic layer was washed with water and brine, and then dried. The ethyl acetate was removed by evaporation, and the residue was chromatographed on a column of silica gel for purification. The fraction eluted with ethyl acetate was concentrated and the residue was crystallized from n-hexane to give 275 mg (yield: 36%) of the titled compound (Ia-1). This was recrystallized from ethyl acetate n-hexane to give colorless crystals melting at 156°˜158° C.

Anal. Calcd. (%) for C₁₆ H₁₃ N₃ O: C, 71.70; H, 5.21; N, 16.72. Found (%): C, 71.62; H, 5.13; N, 16.64.

NMR (DMSO-d₆)δ: 1.05˜1.45 (4H, m), 3.45˜3.75 (1H, m), 4.63 (3H, s), 7.55˜7.85 (2H, m), 8.35˜8.50 (2H, m), 9.40 (1H, s).

EXAMPLE 82-83

In the same manner as in Ex. 81, the objective compounds (Ia) were obtained under the reaction conditions shown in Table 11. The physical properties of the compounds were shown in Tables 12-1 and 12-2.

                                      TABLE 11                                     __________________________________________________________________________      ##STR118##                                                                     ##STR119##                                                                    Amount of                       Compound (Ia)                                  Ex.                                                                               Compd.                                                                              Solvent                                                                              RCOCl     n-BuLiTHF                                                                              Yield Compd.                                   No.                                                                               II-2 (g)                                                                            THF (ml)                                                                             R      (g)                                                                               (ml)                                                                               (ml)                                                                               (mg)                                                                              (%)                                                                               No.                                      __________________________________________________________________________     82 0.55 25                                                                                    ##STR120##                                                                           1.15                                                                              2.5 2   290                                                                               34 Ia-2                                     83 0.55 25    OEt    0.80                                                                              2.5 2   290                                                                               38 Ia-3                                     __________________________________________________________________________

                                      TABLE 12                                     __________________________________________________________________________      ##STR121##                                 (Ia)                                                     Solvent     Elementary Analysis (%)                                            for         Up (Calcd.)                                  Compd.      m.p. Appear-                                                                             Recrysta-                                                                           Molecular                                                                             Down (Found)                                 No.  R      (°C.)                                                                        ance lln. Formula                                                                               C   H    N                                   __________________________________________________________________________     Ia-2                                                                                 ##STR122##                                                                           195-197                                                                             Color- less                                                                         AcOEt                                                                               C.sub.18 H.sub.13 N.sub.3 O                                                           75.25 75.55                                                                        4.56 4.56                                                                           14.62 14.66                         Ia-3 OEt    149-151                                                                             Color-                                                                              AcOEt-                                                                              C.sub.14 H.sub.13 N.sub.3 O.sub.2                                                     65.87                                                                              5.13 16.46                                                less n-Hexane    65.87                                                                              5.10 16.42                               __________________________________________________________________________               Compound                                                                       No.  NMR (CDCl.sub.3) δ                                        __________________________________________________________________________               Ia-2 4.60 (3H,s), 7.40˜7.85 (5H,m), 8.20˜8.50                           (4H,m), 9.40 (1H,s)                                                       Ia-3 1.50 (3H,t), 4.55 (2H,q), 4.63 (3H,s), 7.55˜7.85                         (2H,m), 8.20˜8.45                                                        (2H,m), 9.40 (1H,s)                                             __________________________________________________________________________

EXAMPLES 84-90

In the same manner as in Examples 1, 2, 35, or 36, the objective compounds (Ic) were obtained under the reaction conditions shown in Table 13. The properties of the compounds were shown in Tables 14-1 and 14-2.

                                      TABLE 13                                     __________________________________________________________________________      ##STR123##                                                                    1st Step                                                                                    Amount of Compd. (III)                                                                   Sol-                                                                           vent                   2nd Step                                                                             Compound (Ic)              Ex                     THF                                                                               n-BuliTHF                                                                              RCO-X       CF.sub.3 CO.sub.2 H                                                                  Yield Compd.               No.                                                                               R         R.sup.1                                                                             R.sup.2                                                                          (g)                                                                               (ml)                                                                              (ml)                                                                               (ml)                                                                               X        (g)                                                                               (ml)  (mg)                                                                              (%)                                                                               No.                  __________________________________________________________________________     84                                                                                 ##STR124##                                                                              8-F  H 1.28                                                                              90 2   2   Cl       1.10                                                                              3      50                                                                                6 Ic-71                85                                                                                 ##STR125##                                                                              8-F  H 1.28                                                                              90 2   2   Cl       1.05                                                                              4     470                                                                               56 Ic-72                86                                                                                 ##STR126##                                                                              7-F  H 1.29                                                                              80 2.2 2   OMe      1.1                                                                               4     270                                                                               28 Ic-73                87                                                                                 ##STR127##                                                                              H    H 1.23                                                                              25 2.5 2   Cl       1.70                                                                              4     460                                                                               45 Ic-74                88 (CH.sub.2).sub.2Ph                                                                       7-F  H 1.29                                                                              80 2.2 2   Cl       1.36                                                                              3     155                                                                               16 Ic-75                89                                                                                 ##STR128##                                                                              8-OMe                                                                               H 1.32                                                                              30 2.5 2   Cl       1.04                                                                              4     310                                                                               39 Ic-76                90 CH(CH.sub.3).sub.2                                                                       8-OMe                                                                               H 1.32                                                                              30 2.5 2   OCOCH(CH.sub.3).sub.2                                                                   1.33                                                                              4     630                                                                               78 Ic-77                __________________________________________________________________________

                                      TABLE 14                                     __________________________________________________________________________      ##STR129##                                                 (Ic)                                               Recrysta-       Elementary Analysis (%)        Compd.                m.p.  Appear-                                                                            llizing Molecular                                                                              Up (Calcd.), Down                                                              (Found)                        No.   R.sup.1                                                                            R.sup.2                                                                          R         (°C.)                                                                         ance                                                                               Solvent Formula C  H   N                       __________________________________________________________________________     Ic-71 8-F H                                                                                 ##STR130##                                                                              275-277 (d)                                                                          Color- less                                                                        EtOH    C.sub.16 H.sub.9 N.sub.4 O.sub.2                                               F       60.81 61.02                                                                       3.06 3.28                                                                          18.91 18.81                                                                       F, 6.41 F,                                                                     6.47                 Ic-72 8-F H                                                                                 ##STR131##                                                                              310-312                                                                              Light yellow                                                                       EtOHCHCl.sub.3                                                                         C.sub.16 H.sub.8 N.sub.3 O.sub.2                                               F       64.06 64.03                                                                       2.87 2.93                                                                          14.94 14.92                                                                       F, 6.75 F,                                                                     6.73                 Ic-73 7-F H                                                                                 ##STR132##                                                                              >310  Light yellow                                                                       DMF     C.sub.16 H.sub.19 N.sub.3 O.sub.2                                              FS      61.73 61.56                                                                       3.24 3.40                                                                          13.50 13.44                                                                       F, 6.10 S,                                                                     10.30 F, 6.10                                                                  S, 10.30             Ic-74 H   H                                                                                 ##STR133##                                                                              295-297 (d)                                                                          Light yellow                                                                       EtOHCHCl.sub.3                                                                         C.sub.20 H.sub.12 N.sub.4                                                              70.58 70.78                                                                       3.55 3.69                                                                          16.46 16.26             Ic-75 7-F H (CH.sub.2).sub.2Ph                                                                       274-276                                                                              Color-                                                                             EtOHCHCl.sub.3                                                                         C.sub.19 H.sub.14 N.sub.3                                                              71.46                                                                             4.42                                                                               13.16                                                                             F, 5.95                                          less                71.72                                                                             4.58                                                                               13.31                                                                             F, 6.15              Ic-76 8-OMe                                                                              H                                                                                 ##STR134##                                                                              185-187 (d)                                                                          Color- less                                                                        EtOH    C.sub.16 H.sub.13 N.sub.3                                                              67.41 67.16                                                                       4.90 4.79                                                                          15.72 15.58             Ic-77 8-OMe                                                                              H CH(CH.sub.3).sub.2                                                                       188-190                                                                              Color-                                                                             AcOEt   C.sub.15 H.sub.15 N.sub.3                                                              66.90.2                                                                           5.61                                                                               15.60                                               less                66.89                                                                             5.66                                                                               15.53                   __________________________________________________________________________                                    Compd. No                                                                             NMR (DMSO-d.sub.6)                       __________________________________________________________________________                                           δ                                                                 Ic-71  2.63(3H, s), 7.23(1H, s),                                                      7.50˜7.75(1H, m),                                                        8.10˜                                                                    8.40(2H, m), 9.30(1H, s)                                                Ic-72  7.17(1H, d), 7.47˜7.77(1H,                                               m), 7.93(1H, d), 8.05˜8.45                                               (2H, m), 9.37(2H, s)                                                    Ic-73  2.61 (3H, s), 7.13 (1H, d),                                                    7.55˜7.97 (2H, m),                                                       8.65˜8.85                                                                (2H, m), 9.30 (1H, s)                                                   Ic-74  Measuring Solvent CDCl.sub.3                                                   -CD.sub.3 OD                                                                   7.45˜8.05(8H, m),                                                        8.10˜8.30(1H, m),                                                        8.50˜8.70(1H, m)                                                         9.40(1H, s)                                                             Ic-75  3.07(2H, t), 3.60(2H, t),                                                      7.10˜7.45(5H, m),                                                        7.50˜7.95                                                                (2H, m), 8.55˜8.80(1H, m),                                               9.33(1H, s)                                                             Ic-76  1.35(4H, d), 3.37(1H, quintet),                                                3.97(3H, s) 7.37(1H,                                                           d, d), 7.97-8.20(2H, m) 9.27(1H,                                               s)                                                                      Ic-77  1.30(6H, d), 3.90(1H, septet),                                                 3.97(3H, s), 7.37                                                              (1H, d, ), 8.00˜8.15(2H, m),                                             9.15(1H, s)                              __________________________________________________________________________

REFERENTIAL EXAMPLE 1 1H-Imidazo[4,5-c]quinoline (II-1) ##STR135##

A solution of 5.0 g of 3,4-diaminoquinoline (V-1) in 15 ml of formic acid was refluxed for one hour. The reaction solution was concentrated under reduced pressure, and the residue obtained was neutralized with saturated aqueous sodium hydrogencarbonate. This was allowed to stand overnight. The precipitated crystals were collected by filtration, washed with water, and dried to give 5.6 g of crystals (IV-1). The crystals were suspended in 120 ml of diglyme, and the suspension was refluxed for 1,5 hours. The reaction mixture was cooled down and the precipitated crystals were collected by filtration, and washed with ethyl acetate and n-hexane, successively, to give 5.1 g (yield: 96%) of the titled compound (II-1). This was recrystallized from ethanol to give colorless crystals melting at 294°˜296° C.

Anal. Calcd. (%) for C₁₀ H₇ N₃ : C, 70.99; H, 4.17; N, 24.84. Found (%): C, 71.12; H, 4.27; N, 24.76.

NMR (DMSO-d₆)δ: 7.50˜7.85 (2H, m), 8.03˜8.27 (1H, m), 8.33˜8.57 (1H, m), 8.53 (1H, s), 9.27 (1H, s).

REFERENTIAL EXAMPLES 2-6

In the same manner as in Referential Example 1, the compounds (IV) were obtained under the reaction conditions shown in Table 15. The physical properties of the compounds (II) were shown in Tables 14-1 and 14-2.

                                      TABLE 15                                     __________________________________________________________________________      ##STR136##                                                                     ##STR137##                                                                                1st Step                                                                               2nd Step                                                   Ref.                                                                              Amount of                                                                               Formic                                                                             Reflux   Reflux                                                                             Compound (II)                                     Ex.                                                                               Compound (V)                                                                            acid                                                                               Time                                                                               Diglyme                                                                             Time                                                                               Yield Compd.                                      No.                                                                               R.sup.1                                                                            R.sup.2                                                                          (g)                                                                               (ml)                                                                               (hr)                                                                               (ml) (hr)                                                                               (g)                                                                               (%)                                                                               No.                                         __________________________________________________________________________     2  7-OMe                                                                              H 4.55                                                                              14  1   150  4   4.34                                                                              90 II-2                                        3  6-F H 4.00                                                                              12  1    90  2   3.71                                                                              88 II-3                                        4  7-F H 5.00                                                                              12  1.5 120  1.5 4.97                                                                              94 II-4                                        5  6-Me                                                                               H 1.90                                                                               6  1    70  1.5 1.30                                                                              65 II-5                                        6  6-OMe                                                                              H 2.54                                                                               8  1   100  3.5 2.34                                                                              88 II-6                                        __________________________________________________________________________

                                      TABLE 16                                     __________________________________________________________________________      ##STR138##                                    (II)                            __________________________________________________________________________                           Solvent        Elementary Analysis (%)                                         for      Mole- Up (Calcd.)                               Compd.     m.p.  Appear-                                                                             Recrysta-                                                                               cular Down (Found)                              No.  R.sup.1                                                                            R.sup.2                                                                          (°C.)                                                                         ance lln.     Formula                                                                              C   H    N                                __________________________________________________________________________     II-2 7-OMe                                                                              H 290-292(d)                                                                           Color-                                                                              EtOH     C.sub.11 H.sub.9 N.sub.3 O                                                           66.32                                                                              4.55 21.09                                             less                66.16                                                                              4.76 20.81                            II-3 8-F H 325-327(d)                                                                           Color-                                                                              MeOHCHCl.sub.3                                                                          C.sub.10 H.sub.8 N.sub.3 F                                                           64.16                                                                              3.23 22.44                                             less          64.56 3.48                                                                               22.43                                 II-4 7-F H 316-318(d)                                                                           Color-                                                                              MeOHCHCl.sub.3                                                                          C.sub.10 H.sub.8 N.sub.3 F                                                           64.16                                                                              3.23 22.44                                             less          64.36 3.53                                                                               22.41                                 II-5 8-Me                                                                               H 319-321(d)                                                                           Color-                                                                              EtOH     C.sub.11 H.sub.9 N.sub.3                                                             72.11                                                                              4.95 22.34                                             less                72.15                                                                              5.10 22.71                            II-6 8-OMe                                                                              H 280-282                                                                              Color-                                                                              EtOH     C.sub.11 H.sub.9 N.sub.3 O                                                           66.32                                                                              4.55 21.09                                             less                66.36                                                                              4.74 21.01                            __________________________________________________________________________     Compound                                                                       No.       NMR (DMSO-d.sub.6) δ                                           __________________________________________________________________________     II-2      3.93(3H, s), 7.35(1H, d, d), 7.55(1H, d), 8.33(1H, d), 8.43(1H,                s), 9.17(1H, s)                                                      II-3      7.42˜7.66(1H, m), 8.04˜8.30(2H, m), 8.53(1H, s),                   9.22(1H, s)                                                          II-4      7.48˜7.93(2H, m), 8.40˜8.57(1H, m), 8.53(1H, s),                   9.27(1H, s)                                                          II-5      2.57(3H, s), 7.49(1H, d, d), 8.03(1H, d), 8.27(1H, d), 8.47(1H,                s), 8.17(1H, s)                                                      II-6      3.97(3H, s), 7.30(1H, d, d), 7.83(1H, d), 8.05(1H, d), 8.48(1H,                s), 9.10(1H, s)                                                      __________________________________________________________________________

REFERENTIAL EXAMPLE 7 3-Trityl-3H-imidazo[4,5-c]quinoline (III-1) ##STR139##

To a suspension of 5.2 g of 1H-imidazo[4,5-c]quinoline (II-1) in 180 ml of MeCN were added 10.3 g of trityl chloride and 4.2 g of triethylamine, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with water and brine, and then dried. The ethyl acetate was removed and the residue was chromatographed on a column of silica gel with ethyl acetate-n-hexane (1:1 v/v). Crystallization of the resulting oily substance from n-hexane gave 12.4 g (yield: 98%) of the titled compound (III-1). This was recrystallized from ethyl acetate-n-hexane to give colorless crystals melting at 190°˜192° C.

Anal. Calcd. (%) for C₂₉ H₂₁ N₃ : C, 84.64; H, 5.14; N, 10.21. Found (%): C, 84.58; H, 5.23; N, 10.14.

NMR (CDCl₃), δ: 7.10˜7.50 (15H, m), 7.53˜7.77 (2H, m), 8.07 (1H, s), 8.10 (1H, s), 8.00˜8.20 (1H, m), 8.53˜8.73 (1H, m).

REFERENTIAL EXAMPLES 8-12

In the same manner as in Ref. Ex. 7, the compounds (III) were obtained under the reaction conditions shown in Table 17. The physical properties of the compounds were shown in Tables 18-1 and 18-2.

                                      TABLE 17                                     __________________________________________________________________________      ##STR140##                                                                    Ref.                                                                               Amount of               Reaction                                                                             Compound (III)                               Ex. Compound (II)                                                                             TrCl                                                                               Et.sub.3 N                                                                         MeCN Time  Yield   Compd.                               No. R.sup.1                                                                            R.sup.2                                                                           (g) (g) (g) (ml)  (hr) (g) (%) No.                                  __________________________________________________________________________      8  7-OMe                                                                              H  4.18                                                                               7.10                                                                               3.00                                                                               75    8    8.60                                                                               93  III-2                                 9  8-F H  3.35                                                                               5.99                                                                               2.35                                                                               130  15    6.81                                                                               88  III-3                                10  7-F H  4.50                                                                               8.05                                                                               3.16                                                                               160  24    9.01                                                                               88  III-4                                11  8-Me                                                                               H  1.24                                                                               2.30                                                                               0.95                                                                               40   12    2.68                                                                               97  III-5                                12  8-OMe                                                                              H  2.21                                                                               3.75                                                                               1.58                                                                               40    8    4.75                                                                               97  III-6                                __________________________________________________________________________

                                      TABLE 18                                     __________________________________________________________________________      ##STR141##                                                                                                        Elementary                                                                     Analysis (%)                                                                   Up (Calcd.)                                Compd.     m.p. Appear-                                                                             Solvent for                                                                             Molecular                                                                            Down (Found)                               No.  R.sup.1                                                                            R.sup.2                                                                          (°C.)                                                                        ance Recrystalln.                                                                            Formula                                                                              C  H  N  NMR (CDCl.sub.3)                  __________________________________________________________________________                                                  δ                           III-2                                                                               7-OMe                                                                              H 228-230                                                                             Color-                                                                              AcOEt    C.sub.30 H.sub.23 N.sub.3 O                                                          81.61                                                                             5.25                                                                              9.52                                                                              3.91 (3H, s),                                                                  7.00˜7.60 (17H, m),                                                      8.01                                              less                81.32                                                                             5.34                                                                              9.48                                                                              (2H, s), 8.47 (1H, d)             III-3                                                                               8-F H 267-269                                                                             Color-                                                                              AcOEtCH.sub. 2 Cl.sub.2                                                                 C.sub.29 H.sub.20 N.sub.3 F                                                          81.09                                                                             4.69                                                                              9.78                                                                              7.13˜7.52 (17H, m),                                                      7.97 (1H, s),                                     less                80.67                                                                             4.96                                                                              9.66                                                                              8.03˜8.23 (1H, s),                                                       8.13 (1H, s)                      III-4                                                                               7-F H 226-228                                                                             Color-                                                                              AcOEt    C.sub.29 H.sub.20 N.sub.3 F                                                          81.09                                                                             4.69                                                                              9.78                                                                              7.10˜7.50 (16H, m),                                                      7.63˜7.80                                   less                81.18                                                                             4.78                                                                              9.84                                                                              (1H, m), 8.07 (1H, s), 8.10                                                    (1H, s)                                                                        8.52˜8.68 (1H, m)           III-5                                                                               8-Me                                                                               H 270-272                                                                             Color-                                                                              AcOEt    C.sub.30 H.sub.23 N.sub.3                                                            84.68                                                                             5.45                                                                              9.87                                                                              2.60 (3H, s),                                                                  7.10˜7.60 (16H, m),                                                      7.97                                              less                84.74                                                                             5.44                                                                              9.93                                                                              (1H, d), 8.03 (2H, s), 8.37                                                    (1H, d)                           III-6                                                                               8-OMe                                                                              H 252-254                                                                             Color-                                                                              AcOEt-n-hexane                                                                          C.sub.30 H.sub.23 N.sub.3 O                                                          81.61                                                                             5.25                                                                              9.52                                                                              4.00 (3H, s),                                                                  7.13˜7.50 (17H, m),                                                      7.90                                              less                81.73                                                                             5.38                                                                              9.48                                                                              (1H, d) 7.97 (1H, s), 8.03                                                     (1H, s)                           __________________________________________________________________________

REFERENTIAL EXAMPLE 13 2-Benzyl-8-fluoro-1H-imidazo[4,5-c]quinoline (VII-1) ##STR142##

To a mixture of 10 ml of HMPA and 1 ml of MeCN was added 935 mg of phenylacetyl chloride at -10° C. After stirring at the same temperature for 15 min., 900 mg of 3,4-diamino-6-fluoroquinoline (V-1) was added and the mixture was stirred for 3 hours at -5°˜0° C. The reaction mixture was diluted with ice water and neutralized with saturated aqueous sodium hydrogencarbonate. The crystals precipitated were collected by filtration, dissolved in 200 ml of ethyl acetate and dried. The ethyl acetate was removed and the residue was crystallized from n-hexane to give 1.44 g of the compound (VI-1). The compound (VI-1) was suspended in 50 ml of ethylene glycol and refluxed for 30 min. The mixture was concentrated under reduced pressure. Water was added to the residue. The crystals precipitated were collected by filtration, washed with water, dissolved in 70 ml of ethyl acetate and dried. The ethyl acetate was removed and the residue was crystallized from n-hexane to give 1.3 g (yield: 92%) of the titled compound (VII-1). This was recrystallized from ethyl acetate to give colorless crystals melting at 226°˜228° C.

Anal. Calcd. (%) for C₁₇ H₁₂ N₃ F: C, 73.63; H, 4.36; N, 15,15; F, 6.85. Found (%): C, 73.83; H, 4.30; N, 15.13; F, 6.55.

NMR (DMSO-d₆) δ: 4.33 (2H, s), 7.20˜7.65 (6H, m), 7.93˜8.25 (2H, m), 9.11 (1H, s).

REFERENTIAL EXAMPLES 14-16

In the same manner as in Referential Example 13, the compounds (VII) were obtained under the reaction conditions shown in Table 19. The physical properties of the compounds were shown in Table 20-1 and 20-2.

                                      TABLE 19                                     __________________________________________________________________________      ##STR143##                                                                     ##STR144##                                                                                   1st Step         2nd Step    Compound (VII)                     Ref. Amount of (V)                                                                            HMPA-MeCN                                                                               C.sub.6 H.sub.5 CH.sub.2 COCl                                                          Ethylene                                                                             Reflux                                                                               Yield Compd.                       Ex. No.                                                                             R.sup.1                                                                            R.sup.2                                                                           (g)                                                                               (ml) (ml)                                                                               (g)     glycol (ml)                                                                          Time (hr)                                                                            (g)                                                                               (%)                                                                               No.                          __________________________________________________________________________     14   H   H  0.90                                                                              15   1.5 1.10    50    30    1.15                                                                              79 VII-2                        15   7-F H  0.90                                                                              10   1   0.94    50    10    1.26                                                                              90 VII-3                        16   7-OMe                                                                              H  0.90                                                                              10   1   0.89    30    15    0.74                                                                              54 VII-4                        __________________________________________________________________________

                                      TABLE 20                                     __________________________________________________________________________      ##STR145##                                                                    __________________________________________________________________________                                       Elementary Analysis (%)                                                        Up (Calcd.)                                  Compd.          Appear-                                                                             Solvent for                                                                           Molecular                                                                            Down (Found)                                 No.  R.sup.1                                                                            R.sup.2                                                                          m.p. ance Recrystalln.                                                                          Formula                                                                              C   H    N                                   __________________________________________________________________________     VII-2                                                                               H   H 212-214                                                                             Colorless                                                                           AcOEt  C.sub.17 H.sub.13 N.sub.3                                                            78.74                                                                              5.05 16.20                                                                 78.46                                                                              5.04 15.88                               VII-3                                                                               4-F H 195-196                                                                             Colorless                                                                           AcOEt-n-                                                                              C.sub.17 H.sub.12 N.sub.3 F                                                          73.63                                                                              4.36 15.15                                                    hexane       73.69                                                                              4.39 14.91                               VII-4                                                                               7-OMe                                                                              H 211-213                                                                             Colorless                                                                           AcOEt  C.sub.18 H.sub.15 N.sub.3 O                                                          74.72                                                                              5.23 14.52                                                                 74.63                                                                              5.20 14.39                               __________________________________________________________________________     Compound No.                                                                            NMR (DMSO-d.sub.6) δ                                            __________________________________________________________________________     VII-2    4.33(2H, s), 7.10˜7.50(5H, m), 7.53˜7.80(2H, m),                   7.90˜8.50(2H, m), 9.13(1H, s)                                   VII-3    4.35(2H, s), 7.20˜7.47(5H, m), 7.53˜7.95(2H, m),                   8.25˜8.60(1H, m), 9.17(1H, s)                                   VII-4    3.90(3H, s), 4.30(2H, s), 7.20˜7.57(7H, m), 8.23(1H, d),                 9.07(1H, s)                                                           __________________________________________________________________________

REFERENTIAL EXAMPLE 17 4-Amino-7-fluoro-3-(trichloroacetimidoylamino)quinoline diacetate (VIII-1) ##STR146##

To a solution of 1.77 g of 3,4-diamino-7-fluoro-quinoline (V-4) in 20 ml of acetic acid was added 1.94 g of methyl trichloroacetimidate and the mixture was stirred for two hours at room temperature. After concentration under reduced pressure, 10 ml of ethyl acetate was added to the residue, and the mixture was allowed to stand overnight. The crystals precipitated were collected by filtration and washed with ethyl acetate and then a small quantity of ethanol to give 3.75 g (yield: 87%) of the titled compound (VIII-1).

Melting point: 120°˜125° C. (d)

Anal. Calcd. (%) for C₁₅ H₁₆ N₄ O₄ FCl₃ : C, 40.79; H, 3.65; N, 12.68; F, 4.30; Cl, 24.08. Found (%): C, 40.42; H, 3.90; N, 12.79; F, 4.40; Cl, 24.56.

NMR (DMSO-d₆) δ: 1.90 (6H, s), 7.20˜7.60 (2H, m), 8.17 (1H, s), 8.24 (1H, m).

REFERENTIAL EXAMPLE 18 4-Amino-3-(trichloroacetimidoylamino)quinoline acetate (VIII-2) ##STR147##

In the same manner as in Ref. Ex. 17, 1.59 g of 3,4 -diaminoquinoline (V-1) in 20 ml of acetic acid was treated with 1.9 g of methyl trichloroacetimidate to give 3.13 g (yield: 80%) of the titled compound (VIII-2).

Melting point: 143°˜145° C. (d)

Anal. Calcd. (%) for C₁₃ H₁₃ N₄ O₂ Cl₃ : C, 42.93; H, 3.60; N, 15.40; Cl, 29.24. Found (%): C, 42.88; H, 3.68; N, 15.04; Cl, 29.19.

NMR (DMSO-d₆), δ: 1.90 (3H, s), 7.30˜7.90 (3H, m), 8.13 (1H, m), 8.17 (1H, s).

REFERENTIAL EXAMPLE 19 1-Methyl-1H-imidazo[4,5-c]quinoline (II-2) ##STR148##

A solution of 2.92 g of 3-amino-4-methylaminoquinoline (V-2) in 20 ml of formic acid was refluxed for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between chloroform and saturated aqueous sodium hydrogen-carbonate. The organic layer was washed with brine and dried. The chloroform was removed and the residue was crystallized from n-hexane to give 2.39 g (yield: 77%) of the titled compound (II-2). This was recrystallized from ethyl acetate to give colorless crystals melting at 146°˜148° C.

Anal. Calcd. (%) for C₁₁ H₉ N₃ : C, 72.11; H, 4.95; N, 22.94. Found (%): C, 72.25; H, 4.94; N, 22.86.

NMR (CDCl₃), δ: 4.20 (3H, s), 7.45˜7.80 (2H, m), 7.84(1H, s), 8.15˜8.40 (2H, m), 9.33 (1H, s).

EFFECT OF THE INVENTION

The compounds of the present invention show a high affinity for the benzodiazepine (BZ) receptor in brain. The BZ receptor ligands (compounds bound to the receptor) are thought to comprise a continuous spectrum of agents with a graduated range of pharmacological efficacies at the receptor: (1) full agonists (positive efficacy; anxiolytic/anticonvulsant), (2) partial agonists, selective anxiolytic), (3) antagonists (nil efficacy; antagonism towards the other classes), (4) partial inverse agonists (intermediate negative efficacy; proconvulsant, cognition enhancer), and (5) full inverse agonists (negative efficacy; anxiogenic/convulsant). The classification can be achieved mainly on the basis of inhibition or facilitation of the pentylenetetrazole-induced convulsions [C. Braestrup et al., Biochem. Pharmcol. 33, 859 (1984)]. The inverse agonist methyl β-carbonline-3-carboxylate (β-CCM) enhances the performance in several animal models of learning and memory, whereas the agonist diazepam impairs such performance in humans, suggesting that partial inverse agonists may provide a new type of nootropic drugs [M. Sarter et al., TINS 11, 13 (1988)]. Thus, agonists are exected to work as anxiolytic or anticonvulsant agents, antagonists as antidotes for benzodiazepine intoxication and accidental excessive uptake thereof, and partial inverse agonists as cognition enhancers or nootropic agents.

Experiments of the compounds of the present invention are shown below.

EXPERIMENT 1 Test on Binding to Benzodiazepine Receptor

This test was carried out modifying partially a method of Mohler & Okada, Science, 198, 849-851 (1977). Receptor preparation was provided from the cerebral cortex of male Wistar rats (11-13 weeks age). Inhibitory action of the test compound on the specific binding of tritium-labeled diazepam to the receptor was evaluated as follows: 2 nM tritium-labeled diazepam and an aqueous solution of the test compound in 5 or 6 different concentrations were incubated with the receptor preparation at 0° C. for 60 minutes. The 50% inhibitory concentration (IC₅₀) was measured by the concentration-response curve. In addition, the inhibitory constant (Ki) of the test compound was calculated by dissociation constant (Kd) and concentration (L) of the tritium-labeled diazepam. The results are shown in the undermentioned table.

    ______________________________________                                          ##STR149##                                                                           Test    Ki                                                                     Compound                                                                               (nM)                                                            ______________________________________                                                Ic-1    0.357                                                                  Ic-4    0.409                                                                  Ic-6    0.432                                                                  Ic-9    6.11                                                                   Ic-14   1.24                                                                   Ic-18   3.60                                                                   Ic-21   0.50                                                                   Ic-22   1.90                                                                   Ic-27   13.1                                                                   Ic-31   1.50                                                                   Ic-37   2.21                                                                   Ic-41   8.33                                                                   Ic-45   3.20                                                                   Ic-49   1.80                                                                   Ic-50   0.819                                                                  Ic-56   1.07                                                                   Ic-60   0.373                                                           ______________________________________                                    

EXPERIMENT 2 Anatagonism of Pentylenetetrazole-Induced Convulsion

Agonistic activity was evaluated in this Experiment. Pentylenetetrazole was subscutaneously administered male mice (a group of 8-16 male mice was employed in each test) at a dose of 125 mg/kg immediately after intravenous injection of the test compound. The dose (ED₅₀) required to prevent tonic convulsion and death in 50% of the animals during subsequent 2-hour observation period was calculated by the probit method.

    ______________________________________                                                        ED.sub.50                                                       Test Compd.    (mg/kg)                                                         ______________________________________                                         Ic-9           3.21                                                            Ic-27          2.47                                                            Ic-36          0.46                                                            Ic-38          1.12                                                            Ic-45          0.88                                                            Id-2           1.06                                                            ______________________________________                                    

EXPERIMENT 3 Potentiation of Pentylenetetrazole-Induced Convulsion

Inverse agonist activity was evaluated in this Experiment. Pentylenetetrazole was subscutaneously administered male mice (a group of 8-16 male mice was employed in each test) at a dose of 90 mg/kg immediately after intravenous injection of the test compound. The dose (ED₅₀) required to produce tonic convulsion and death in 50% of the aminals during subsequent 2-hour observation period was calculated by the probit method.

    ______________________________________                                                        ED.sub.50                                                       Test Compd.    (mg/kg)                                                         ______________________________________                                         Ic-6           1.00                                                            Ic-14          0.20                                                            Ic-22          0.15                                                            Ic-24          0.09                                                            Ic-60          0.71                                                            Ic-64          0.31                                                            Ic-67          0.35                                                            ______________________________________                                     

What we claim is:
 1. A compound of the formula: ##STR150## wherein R is (1) hydrogen, (2) C₁ -C₁₀ alkyl optionally substituted by halogen, C₁ -C₅ alkylthio, C₁ -C₅ alkyloxycarbonyl, or phenyl, (3) C₃ -C₅ cycloalkyl optionally substituted by C₁ -C₅ alkyl, (4) C₂ -C₅ alkenyl optionally substituted by C₁ -C₅ alkyl or di-C₁ -C₅ alkyl (5) amino optionally substituted by C₁ -C₅ alkyl or di C₁ -C₅ alkyl, (6) phenyl optionally substituted by one or two members independently selected from the group consisting of halogen, trifluoromethyl, C₁ -C₅ alkoxy, and C₁ -C₅ alkylthio, or (7) a isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thienyl, furyl or pyridyl each optionally substituted by one or two members independently selected from the group consisting of halogen, C₁ -C₅ alkyl, and phenyl; Q is hydrogen, C₁ -C₅ alkyl, benzyl, benzhydryl, trityl, C₁ -C₁₃ acyl, C₁ -C₅ alkylsulfonyl, or C₆ -C₁₂ arylsulfonyl, provided that Q is located at the nitrogen atom of the 1-, 3-, or 5-position; R¹ and R² each is a hydrogen, C₁ -C₅ alkyl, C₁ -C₅ alkoxy, or halogen; and the dotted lines indicate the presence of three double bonds at positions 2(3), 3a(9b), 4(5); 1(9b), 2(3), 3a(4); or 1(2), 3a(9b), 4(5); or a pharmaceutically acceptable acid addition salt thereof.
 2. A compound claimed in claim 1, namely 2-cyclopropylcarbonyl-7-fluoro-1H-imidazo[4,5-c]quinoline.
 3. A compound claimed in claim 1, namely 2-cyclopropylcarbonyl-7-methoxy-1H-imidazo[4,5-c]quinoline.
 4. A pharmaceutical composition for treatment of depression, convulsion, anxiety, amnesia, senile dementia, or cerebral disorder, comprising a pharmacologically effective amount of a compound according to claim 1 together with a carrier, diluent, and/or excipient.
 5. A method for treating a patient suffereing from depression, convulsion, anxiety, amnesia, senile dementia, or cerebral disorder characterized by administering a pharmaceutical composition according to claim 4 to the patient.
 6. A compound claimed in claim 1, namely 2-isobutyryl-7-fluoro-1H-imidazo[4,5-c]quinoline.
 7. A compound claimed in claim 1, namely 2-butyryl-1H-imidazo[4,5-c]quinoline.
 8. A compound claimed in claim 1, namely 2-(4-fluorobenzoyl)-1H-imidazo[4,5-c]quinoline. 